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Which CLL Treatment Is Right for You? What You Need to Know

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Which CLL Treatment Is Right for You? What You Need to Know from Patient Empowerment Network on Vimeo. 

What do you need to know before deciding which treatment is best for YOUR CLL? Dr. Lindsey Roeker discusses the role of key CLL tests, including biomarker testing, reviews emerging research, and provides tips for partnering with your care team to advocate for the best care. 

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An Overview of CLL Treatment Types

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Transcript:

Katherine:

Hello, and welcome. I’m Katherine Banwell, your host for today’s program. Today we’re going to discuss how to access the most personalized CLL treatment for your individual disease, and why it’s essential to insist on key testing. Before we meet our guest, let’s review a few important details. The reminder email you received about this program contains a link to program materials. If you haven’t already, click that link to access information, to follow along during the webinar.

At the end of this program, you’ll receive a link to a program survey. Please take a moment to provide feedback about your experience today, in order to help us plan future webinars. And finally, before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you. Joining me today is Dr. Lindsay Roeker. Dr. Roker, thank you so much for joining us. Would you introduce yourself?

Dr. Roeker:                 

Absolutely. So, my name is Lindsey Roeker, and I am a member of the CLL program at Memorial Sloan-Kettering Cancer Center in New York City.

Katherine:                  

Excellent, thank you. Let’s start at the beginning. How is CLL diagnosed?

Dr. Roeker:                 

Absolutely. So, for most patients, CLL is diagnosed after a routine blood test shows a high white blood cell count. That’s kinda the most common way that we find people entering into our clinic. Other things that people can notice is they have lumps or bumps that they’ve felt in their neck or under their armpits. Those are some other symptoms that can lead to the diagnosis, but often once a patient finds that their white blood cell count is high, some additional testing is done, and the diagnosis of CLL is made.

Katherine:                  

What are some common symptoms of CLL? You mentioned the lumps and bumps.

Dr. Roeker:                 

Yeah. So, often in early stages, the lumps and bumps in the neck are the most common that people recognize, but fevers or chills, night sweats, where patients are waking up drenched, having to change their pajamas, or weight loss without trying, are some other symptoms that can raise some alarm bells and make people start looking for something.

 And CLL can be a diagnosis that can be found through that, as well.

Katherine:                  

What is watch and wait?

Dr. Roeker:                 

So, after diagnosis, about two-thirds of patients enter this period of watch and wait, and what that means is we have good data to say that treating CLL before it’s causing symptoms doesn’t help people live better or live longer. And for that reason, we use the approach of watch and wait, and what that really means is you see your doctor a few times a year. I see people every three to four months. And you have your labs checked, have a physical exam, and through that process, just ensure that there are no symptoms that the CLL is causing that warrant therapy.

Katherine:                  

That’s very helpful. Thank you for that. Now, what tests are necessary to help understand a patient-specific disease, both at diagnosis and prior to treatment?

Dr. Roeker:                 

So, a diagnosis flow cytometry is the first test done, and what that means is, you take all of your white blood cells in your blood, and you run them through a fancy machine that puts them into buckets. So, you have a bucket of your normal neutrophils, a bucket of your normal lymphocytes, and then you find this bucket of cells that look somewhat unusual. And those have a specific look, if you will, and if they look like CLL cells, that’s how we make the diagnosis.

As you start reading, you’ll find that people talk about monoclonal B-cell lymphocytosis, which is MVL, CLL, and SLL, and a lot of times, it’s confusing because you start reading, and there are all of these – kind of lingo around it. So, what we’re looking for with flow cytometry is how many cells are in the peripheral blood? If it’s fewer than 5,000 per microliter – so, your doctor will talk to you; they’ll either say five or 5,000, depending on what units they’re using.

If it’s lower than that, and you don’t have any lumps or bumps or lymphadenopathy, meaning enlarged lymph nodes, that’s when we make the diagnosis of monoclonal B-cell lymphocytosis.

So, that’s kind of a pre-cancer diagnosis. Then, CLL, the diagnosis, is made in any patient who has greater than 5,000 cells per microliter, or five, if you’re using that unit, and that’s when the diagnosis of CLL is made. If people have lymph nodes that are enlarged, and there are CLL or SLL cells inside of them, but not a lot of involvement in the blood, that’s when we make the diagnosis of SLL, which is small lymphocytic lymphoma. So, CLL and SLL are really the same disease; it’s just where they manifest, primarily. So, whether it’s mostly in the blood, that’s CLL, or mostly in the lymph nodes, and that’s SLL.

Dr. Roeker:                 

Nope. So, that’s the flow cytometry test, and that’s kind of the test that leads to the diagnosis.

Katherine:                  

Got it. What about FISH and TP53 mutation?

Dr. Roeker:                 

So, at diagnosis, I often do this testing. Depending on which provider you go to, you may do it at diagnosis or closer to the time of needing treatment. But FISH is basically a test that looks for big changes in the chromosomes. So, if you remember back to high school biology and you see all of those chromosomes laid out, what FISH is looking for is big changes in those chromosomes. So, is there an entire arm of one of the chromosomes missing? And that’s what FISH does.

There’s also something called karyotyping, or in some institutions, they use something called SNP array. These are more refined tests that look for additional changes in the DNA. So, FISH is kind of a targeted look at a few different chromosomes, whereas karyotype or SNP array looks at all of the chromosomes. Then, there is TP53 mutational testing, and that is done through a bunch of different testing, often next-generation sequencing is what we use.

And we basically use a fancy spellcheck to see if there’s any misspellings, if you will, in TP53.

And TP53 is a gene that we use. It’s called the guardian of the genome. So, its job is basically to make sure that our cells are reproducing. They keep all the genes in working order. If TP53 is missing or misspelled, it doesn’t work as well, and that’s when people can get more issues with their CLL. It tends to be CLL that behaves a little more aggressively.

Katherine:                  

What about IGHV mutation status?

Dr. Roeker:                 

So, IGHV mutation status is a really important feature because it really is, of all of the things, what helps us understand the best way to go about therapy. And IGHV mutational status is basically a signature of the CLL that helps you understand how mature or immature the CLL cells are.

In general, mature cells tend to behave a little bit more predictively, and in ways that behave a bit better with therapy. So, the more mature cells are actually mutated IGHV, and I know that’s backward, because usually we think of mutated as being back. But in this case, mutated is actually those cells that are a bit more mature, and that just has to do with how white blood cells develop in our body. If it’s IGHV-unmutated, those tend to be the more immature cells that can behave a little more erratically.

Katherine:                  

Which tests need to be repeated over time?

Dr. Roeker:                 

So, IGHV mutational status never changes, so that one does not need to be repeated. TP53 mutational status, FISH, and karyotype or SNP array, are ones that I tend to repeat before we start any therapy. So, at the time that you’re going to start your frontline therapy, and then if you have the disease come back and need to be treated again, I usually repeat those tests because those can change over time.

So, that’s both FISH, karyotype or SNP array, and the TP53 mutational testing.

Katherine:                  

Okay. So, it sounds like it’s important for patients to make sure they’ve had this testing. What do the test results reveal about a patient’s prognosis?

Dr. Roeker:                 

So, IGHV mutational status, like I said, really helps us understand how to approach therapy. In general, CLL is a disease that we are increasingly managing with targeted medicines, so drugs that really manipulate the cell biology to either stop the growth of cells or kill the cells so that they pop open. And that has been a trend that has taken place over the last six or seven years, and definitely has revolutionized the treatment of CLL. There is still a small minority of patients, the patients who have IGHV-mutated disease, and are younger, and have fewer other medical problems, that can still be good candidates for chemotherapy.

And the reason that I say that is because in general, chemotherapy for those young, mutated patients cures a subset of patients, so when we look at long-term studies of FCR, which is a combination of chemo and immunotherapy, there are a subset of patients who have a really long period where their disease doesn’t come back, to the point that we call them cured or functionally cured. That’s obviously a word that has a lot of emotional charge around it, and it’s hard because there’s always the possibility of the disease coming back in the future.

But because of those long-term outcomes, we know that there’s some patients that can really have long-term benefit from chemoimmunotherapy.

For IGHV-unmutated patients, and especially for patients with TP53 mutations or deletion of 17p, chemoimmunotherapy really is not the right answer, with all of the medications that we have available to us now.

Katherine:                  

We have an audience question. Mike wants to know, “What does it mean to have high-risk CLL?”

Dr. Roeker:                 

So, great question, and the interesting thing is that I think the answer to that question is evolving. So, deletion of 17p, deletion of 11q, and TP53 mutation have historically been markers of more aggressive disease or unfavorable CLL. In the era where we only had chemo and immunotherapy, we know that patients had less great outcomes. We know that the treatments tended to not work as well, and patients had disease that tended to come back faster, and things like that.

 That’s all evolving in the era of targeted agents. We have some indication that probably patients who have more aggressive underlying disease biology, meaning disease that’s going to behave less well, kind of regardless of what we treat it with, certainly may derive less benefit, meaning that the treatment will work for less long. That being said, these treatments are still really effective for our patients who have traditionally high-risk disease. So, I think it still remains to be seen, in terms of long-term outcomes and what to expect for patients that have these traditionally high-risk characteristics.

Katherine:                  

So, now that we understand how these tests affect prognosis, let’s discuss how they can affect treatment options. Let’s run through a few potential results so we can understand how you might approach each patient type. If someone has deletion 17p, what is the approach?

Dr. Roeker:                 

So, there are two totally reasonable frontline treatment options.

So, BTK inhibitors, which are – the current approved ones are ibrutinib and acalabrutinib, are completely a reasonable approach in the frontline setting, meaning the first treatment that someone gets, and those are pills that you take daily. For ibrutinib, it’s once a day. For acalabrutinib, it’s twice a day, for as long as they’re working. And the idea is, with this approach, you keep on those medicines, and they keep the disease suppressed. So, that’s the first option.

The second totally reasonable option is a combination of venetoclax and obinutuzumab. So, venetoclax is a pill and obinutuzumab is an IV medicine, and the way that this was studied was a total of one year of therapy. So, from the time you start until you’re done with all of your treatments, that’s a one-year course. And the drugs have different side effect profiles, and depending on other medical problems, patient preference about, let’s just take a pill and that’s easy, versus the combination of pill and IV medicines, either can be a completely reasonable choice.

It just depends a lot on patient and doctor preference.

Katherine:                  

What about the TP53 mutation?

Dr. Roeker:                 

So, both of those treatment options seem to work very well for TP53-mutated patients. We had that discussion about the possibility of chemoimmunotherapy for a small minority of patients, and for patients with a TP53 mutation, using chemoimmunotherapy up front is probably not the correct answer. It’s better to go with one of the targeted drug approaches.

Katherine:                  

You mentioned, Dr. Roeker, the IGHV mutated and unmutated. How would you approach each patient type, if a patient is IGHV unmutated?

Dr. Roeker:                 

So, IGHV-unmutated is the same discussion. Chemoimmunotherapy is probably not going to provide a durable, meaning it’s not going to last for a long time. We’re not going to achieve that potential cure. So, for those patients, either the BTK inhibitor approach, or the venetoclax/Obinutuzumab approach is completely a reasonable one to take.

Katherine:                  

And if they’re IGHV-mutated?

Dr. Roeker:                 

IGHV-mutated patients who are young and don’t have a lot of other medical problems, that’s when we add in the third option of chemoimmunotherapy. For many patients, it’s not wrong to choose either a BTK inhibitor or venetoclax/Obinutuzumab, but it does add in that third potential option of chemoimmunotherapy.

Katherine:                  

Are there other markers that patients should know about?

Dr. Roeker:                 

I think those are the big ones.

So, TP53 mutation status, FISH, and karyotype kind of gets you most of them. Some centers do additional next-generation sequencing of other genes that have been associated with higher-risk disease, though really understanding how to interpret those results still remains somewhat unclear, and that’s still an area of research that people are doing, to really understand what those other mutations really mean for people.

Katherine:                  

What about the impact of testing, overall? Why is it so important?

Dr. Roeker:                 

So, as we’ve moved from a disease that was really only treated with chemoimmunotherapy, to one that has targeted drugs available, knowing your IGHV mutational status really impacts what your frontline treatment options are. That’s the major therapy-defining risk factor. The other mutations help you know what to expect. So, for patients who have deletion of 17p or TP53 mutation, it’s possible that the treatments are going to, overall, work for a shorter period of time.

All that being said, every person is an individual, and it’s hard to predict exactly how long someone’s going to respond, from an individual basis. So, what I tell my patients is, “I could tell you what 100 of people with exactly your same disease would do, on average, but I can’t tell you exactly what’s going to happen for you. And that’s a journey that we’re going to take together and really understand over time.”

Katherine:                  

These are really great points, Dr. Roeker. Now, we’ve talked about this a little bit. What are other important factors to consider, like a patient’s age, that can help them access the best treatment for their CLL?

Dr. Roeker:                 

So, age is important. Other medical problems is actually a very important consideration.

So, these medications have different side effect profiles and behave differently in different people. So, the BTK inhibitors, specifically ibrutinib is the one that we have the most data on, has cardiovascular side effects, so it can cause atrial fibrillation. It can cause high blood pressure. So, for patients who have preexisting heart disease, or preexisting atrial fibrillation that has been hard to control, or blood pressure that has been hard to control, for those people, I think adding in a BTK inhibitor can be a bit more of a higher risk situation than in somebody without those preexisting problems.

Venetoclax is a pill that causes the cell to burst open rapidly, and it kills cells very quickly. Because of that, the major side effect is called tumor lysis syndrome, and tumor lysis syndrome is basically the cell opens up and all of the salt inside of it goes into the bloodstream.

And that salt can actually be really hard on the kidneys. So, for people who have kidney problems, venetoclax can be somewhat more challenging to use and just requires a higher level of vigilance. So, for patients who have preexisting kidney disease or the idea of a lot of monitoring and things like that, is more challenging. Then maybe the BTK inhibitors are a better choice.

Katherine:                  

How do you monitor whether a treatment is working?

Dr. Roeker:                 

So, a lot of it has to do with the CBC, so your normal blood count, and what we’re looking for is improvement in hemoglobin and improvement or normalization of platelet count. And for many people, those, either anemia or low platelets, are the symptoms that drive people to be treated in the first place, so we’re looking for those parameters to get better.

With a lot of people with CLL, totally understandably, because it’s the number that’s the most abnormal, really focused on white blood cell count. 100% understandable.

I always tell people that that’s actually the part of the CBC that I care least about, and the reason is that, for patients on BTK inhibitors, we expect to see the white blood count actually get higher before it gets less high. That’s actually just a sign that the drug is working and it’s pulling CLL cells from the lymph nodes into the bloodstream. So, that’s actually a good sign that it’s working, and that lymphocyte count, at least in the beginning, isn’t a great marker of how well the drug is working.

The other thing that’s important is the physical exam, so looking for whether any lymph nodes that were enlarged have normalized or gone away, and also feeling the sides of the spleen, because the spleen can become enlarged with CLL, and it’s important to make sure that’s normalizing, as well.

And then the last piece is talking to people, so making sure that if they were having fatigue, or fevers, or night sweats before they started treatment, to make sure that those symptoms have gone away. And that’s kind of the three things that I use. I use the blood counts, the physical exam, and the interview with a patient to really understand how their disease is responding.

Katherine:                  

Dr. Roeker, why is it important for patients to speak up if they’re experiencing side effects? I know that they sometimes feel like they’re bothering their healthcare team.

Dr. Roeker:                 

Thank you for that question, because it’s really important point. Side effects are easiest to manage when you catch them early. So, when people have, for instance, muscle pain or joint aches, I have lots of tricks up my sleeve to help people, but I need to know about it. So, if people don’t tell me until they have joint pain that’s so bad that they’re not able to exercise or not able to get out of bed easily in the morning, that’s taking it – it’s gone on for a while at that point, and it’s pretty far down the line.

First of all, you wouldn’t have had to suffer for that long because we have ways of fixing it, and second, it’s always harder to fix a problem once it’s further down the line than earlier on. So, I talk to people about what side effects they might experience and what to expect, and then we talk about different management strategies to really nip it early so that we’re not dealing with a really huge problem down the line.

Katherine:                  

We have a question from our audience. Maria asks, “I just found out that I will need to undergo treatment again. I was previously treated with FCR. Does that impact my options now, going forward?”

Dr. Roeker:                 

Great question. So, FCR was a really common treatment strategy before we had all of the drugs that we have available now. We have good data to say that both BTK inhibitors and venetoclax-based treatments work after chemoimmunotherapy. In fact, those were the patients in whom these drugs were really initially studied, so we actually know better in that group of patients how they’re going to work, than in the patients who have never been treated with them, in terms of the amount of data and the long-term follow-up that we have.

So, most likely, your provider will still talk to you about kind of the two therapeutic option being a BTK inhibitor-based approach versus a venetoclax-based approach, and either are completely appropriate in that setting.

Katherine:                  

We have another question from our audience. Eileen is currently in active treatment for her CLL, and she wants to know, “Is the COVID-19 vaccine safe for her?”

Dr. Roeker:                 

Great question. So, here is my take on COVID vaccines. We have great data on the safety of these vaccines, so the risk of a life-threatening allergic reaction is very, very low, less than one in a thousand. We know that it can cause some irritation at the injection site, so pain in your arm. We know that it can cause some kinda flu-like, blah symptoms for a couple of days, totally fine to take ibuprofen and kinda get yourself through that period.

But from a safety perspective, I don’t have concerns about these vaccines. There’s a lot of social media coverage on long-term implications that are either not based on data, at all, and just speculation, and people who are trying to raise alarm, or people who are really bringing up bad things that are happening to people really far out from the vaccine. And I think it’s really hard to attribute that to the vaccine. Obviously, any time there is a new technology, there’s the possibility of things happening, and we’re going to know more with time, but I think, overall, from a scientific perspective, there is no data that makes me worried about the safety of this vaccine.

The efficacy question, I think, is more of an open question, and the reason I say that is two-fold. The first is, we know that patients with CLL who get other vaccines, some get 100% coverage, some get zero percent coverage, and some are somewhere in between.

And it’s hard to predict who is going to fall where. So, that’s the first piece. The second piece is, we’ve looked at patients who had CLL and got COVID, and we saw if they made antibodies, which is kind of a marker of an immune response, and it’s not consistent that every patient who got COVID makes antibodies.

So, the combination of those two pieces of data makes me question exactly how well they’re going to work. So, what I’m telling my patients is, “Definitely go ahead and get it. I think it’s safe. And then pretend that you didn’t get it.” So, I know that’s hard advice to hear, but continue wearing a mask, continue social distancing, and continue to wash your hands. And then, every interaction you have is a risk-benefit discussion or decision. So, that’s different for every person, but in general, I recommend that people continue being cautious.

Once the whole population around you is vaccinated and we have less virus circulating in the community, that’s when it’s going to be substantially safer. So, definitely, I recommend that people get it, regardless of whether you are on watch and wait, getting treatment, have just finished treatment, whatever it is, but I do think there’s reason to be cautious even after getting vaccinated.

Katherine:                  

Are there symptoms or issues CLL patients should be looking out for, post-vaccine?

Dr. Roeker:                 

Not particularly, beyond what people are getting in kind of the general population. If you’re having a lot of those kind of flu-like symptoms, just talk to your provider to make sure that ibuprofen is safe, because if your platelets are really low, that can cause bleeding. But Tylenol is typically pretty safe, and talk to your doctor about which medicines are kinda best for you to take in that situation, but no particular concerns in patients with CLL.

Katherine:                  

Okay. Thank you for the clarification. As I mentioned at the start of this program, patients should insist on essential CLL testing. As we conclude, I think it’s important to point out that some patients may not know if they’ve received these important tests, so how can they take action?

Dr. Roeker:                 

So, the next time you’re at your doctor, ask, “I just want to know more about the prognosis of my CLL, and can we talk through the genetic markers of my disease, to help me understand what to expect?” That’s kind of code for, “Let’s go through all of these test results,” and it also – if you have a provider who doesn’t routinely test them at diagnosis, and for instance, just tests before treatment, they can also kind of give you their sense of when they do the testing, so you know what to expect. And I think that’s an important discussion to have with your provider, for sure.

Katherine:                  

Are there key questions that patients should ask their physicians?

Dr. Roeker:                 

I’m always impressed with the questions that people come up with. I think one of the best is, what should I expect, based on what we’re doing now? It’s always a hard question to answer because, obviously, for any patient, it’s so individualized, but I think understanding what to expect, as a general sense, is a good way to approach both treatment and prognosis, and all of those kinds of things.

Katherine:                  

I’d like to close by asking about developments in CLL research and treatment. What’s new that you feel patients should know about?

Dr. Roeker:                 

So, there are a lot of exciting drugs coming up in CLL. We have the BTK inhibitors, ibrutinib and acalabrutinib approved. We have more BTK inhibitors with different side effect profiles that are in development.

And there’s also a new class of drugs called noncovalent BTK inhibitors, which seem to work well, even when prior BTK inhibitors have stopped working. So, that’s a really exciting development. There is also just lots of studies about how we combine drugs to maximize efficacy while minimizing side effects, and all of these studies that are underway are really looking at refining how we approach treatment so that we can treat people very effectively but also minimize their side effects.

And as we have more results available, the treatment paradigm for CLL is going to continue to shift and evolve, and I think there are a lot of exciting things coming, and there’s definitely a lot of reason to be hopeful, that the future of CLL is even brighter than the present.

Katherine:                  

It all sounds very promising, Dr. Roeker. Thank you so much for joining us today.

Dr. Roeker:                 

Thank you so much for having me. I really appreciate it.

Katherine:                  

And thank you to all of our partners. If you would like to watch this webinar again, there will be a replay available soon. You’ll receive an email when it’s ready. And don’t forget to take the survey, immediately following this webinar. It will help us as we plan future programs. To learn more about CLL and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us.

An Overview of CLL Treatment Types

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An Overview of CLL Treatment Types from Patient Empowerment Network on Vimeo.

What are the treatment types for chronic lymphocytic leukemia (CLL)? Dr. Matthew Davids details each type of treatment – and which type of patients some treatments may be most appropriate for. 

Dr. Matthew Davids is Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute. Learn more about Dr. Davids here.

See More from Engage CLL

Related Resources:

 

How Can CLL Patients Be Active in Their Care Decisions?

Transcript:

Katherine:

Well, once it’s time to treat, of course, then it’s time to think about treatment options. Let’s walk through the types of treatments that are used today to treat CLL.

Dr. Davids:

As I alluded to before, we historically have had chemotherapy-based approaches to treat CLL. And that was an effective way to temporarily put the disease into remission, but it had a lot of side effects and inevitably the CLL would come back. And the challenge particularly with chemotherapy-based approaches it that when the CLL does come back after chemotherapy, it tends to behave more aggressively and be harder to treat.

So, there have been quite a few studies over the last few years trying to figure out ways that we can avoid using chemotherapy as the first treatment, and this can involve treatments such as monoclonal antibodies. People may have heard of rituximab or a newer drug, obinutuzumab. There are the inhibitors of the B-cell receptor pathway, and this is for example ibrutinib (Imbruvica), which targets a protein called BTK, also a newer one called acalabrutinib (Calquence), which targets BTK. And then, I mentioned at the beginning these fixed-duration therapies that stop after a period of time. Many of those are based on a newer oral drug called venetoclax (Venclexta), which when we give it as a first therapy, we give in combination with that antibody obinutuzumab (Gazyva).

So, a bit of an alphabet soup. I know it gets confusing with all the different treatments, but the good news for CLL patients is, 1.) we have a lot of options, which is great, 2.) we don’t necessarily need to use chemotherapy anymore, and in fact I use it pretty rarely these days. One situation where I do still consider chemotherapy is for younger patients – which in the CLL world is sort of under age 60 or so – if they have very favorable biology to the disease, in particular this mutated IGHV.

That’s a scenario where the older chemotherapy regimen, FCR, can be very effective. It’s a six-month treatment, and we have patients with those molecular characteristics who are now 12, almost 15 years out from their initial six months, and they’re still in a complete remission. So, many of those patients have been functionally cured of their CLL from the six months of treatment. But again, there are some risks to that approach. We worry about other cancers that may be more likely after receiving FCR. We worry about infections, and particularly in the COVID situation, we worry about COVID infection in patients on chemotherapy.

So, it’s been pretty rare that I’ve been using that approach these days. I’ve been opting more for the novel agent-based approaches. So, often now the conversation as an initial therapy comes down to, “Do you prefer more of a continuous treatment strategy with a BTK inhibitor drug like ibrutinib or acalabrutinib, or do you like the idea of a time-limited therapy with one year of venetoclax in combination with obinutuzumab?” And I would say there’s pros and cons to both approaches, and we don’t know which one is the optimal one for CLL patients to start with, but probably I think most patients at some point in their lifetime are going to need one therapy or the other.

So, maybe in the end it doesn’t matter too much which one you start with if you’re going to get both eventually anyway. But we don’t know that yet.

AML Research Updates: News from ASH 2020

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AML expert Dr. Jeffrey Lancet shares news from the 2020 American Society of Hematology (ASH) annual meeting. Dr. Lancet sheds light on headlines from the meeting including FLT3 inhibitor research, combination therapies with venetoclax, a promising inhibitor therapy, and shares his optimism about the future of AML treatment.

About the Guest:
Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

See More From INSIST! AML

Transcript

Katherine:

Hello and welcome, I’m Katherine Banwell. Today we’ll discuss the latest news from ASH 2020 and how AML patients can advocate for personalized care. Joining me is Dr. Jeffrey Lancet. Welcome, would you please introduce yourself?

Dr. Lancet:

Hi, sure. My name is Dr. Jeff Lancet. I’m at the Moffitt Cancer Center in Tampa, Florida where I am the Chair of the Malignant Hematology Department. We spend a lot of time treating patients and conducting clinical trials of Acute Myeloid Leukemia.

Katherine:

Dr. Lancet, the American Society of Hematology annual meeting just closed. What are the AML headlines from this year’s meeting?

Dr. Lancet:

Yeah, so as usual AML was a very busy area for clinical presentations this year at the ASH meeting focusing largely on novel and targeted therapies. I don’t believe that there were many practice changing delevelopments, per se, but rather discussions about many promising therapeutic strategies that are still under development and moving forward rapidly largely in the areas of targeted therapy, low intensity therapy, measurable residual disease, and things of that nature.

Katherine:

What does this research news mean for patients?

Dr. Lancet:

Well, I think that there is a lot to be encouraged about and maybe I’ll take the time to review some of the highlights in what was presented with respect to some of the novel therapeutic approaches that many of our patients can look forward to receiving in the not-too-distant future.

So we often talk about targeted therapy instead of, of course, one of the major targets over the years has been that of a mutated FLT3, which is one of the most common mutations in AML.

And at this meeting, we saw several presentations on clinical trials results utilizing Inhibitors of FLT3 with some emphasis on the most recently approved 2nd generation drug called gilteritinib.

There were, I thought, three major presentations focusing on gilteritinib. One was an update on a randomized phase 3 trial comparing gilteritinib plus azacitidine versus azacitidine alone in newly diagnosed unfit for induction chemotherapy patients with FLT3 mutations. Preliminary showing good tolerability and high composite complete response rates in the combination arm. 

There was another trial of gilteritinib plus venetoclax in relapsed refractory FLT3 mutated AML and what was interesting was that a very high percentage of patients achieved response with this combination of gilteritinib plus venetoclax. Many of whom were heavily pre-treated previously and many of whom had also got prior FLT3 inhibitor therapy during an earlier stage of the disease, so the combination of gilteritinib plus venetoclax in this more refractory setting was encouraging to see these promising responses.

And then we say some data reporting the effects of gilteritinib in combination with more traditional chemotherapy induction with a couple of studies demonstrating both high complete response rates, as well as high rates of mutation clearance of the FLT3 mutation. So those are very encouraging data that were presented with respect to the FLT3 mutated AML population. 

So another very important drug that reached the marketplace for AML recently is a drug called venetoclax, which is an inhibitor of a protein called BCL2. And this drug was recently FDA approved for use in combination with low-intensity chemotherapy drugs such as azacitidine or decitabine. And it seems as though the combination of venetoclax plus one of these hypomethylating agent drugs, azacitidine or decitabine, has resulted in very strong efficacy signals as recently published in the New England Journal of Medicine paper that reported on the results of the Phase 3 trial of venetoclax plus azacitidine.

So that has now become standard of care for older, less fit adults with newly diagnosed AML. The combination of venetoclax plus hypomethylating agent such as azacitidine. And naturally there’s been interest in really kind of taking it several steps further to advance the role of these combinations and to also look at additional drugs in combination with venetoclax plus hypomethylating agent therapy. So, we saw some of that at the ASH meeting this year.

One approach would be to take venetoclax and then to combine it with more intensive chemotherapy for perhaps more fit patients or younger patients that could undergo a more intensive program. So we saw presentations of venetoclax being combined with a drug called CPX-351 which is a novel liposomal formulation of two common chemotherapy drugs that had been approved a few years ago for secondary AML. And we also saw a combination strategy with venetoclax and a regimen known as FLAG-IDA, which is a commonly used induction regimen in Acute Myeloid Leukemia.

I think it’s important to recognize that although these trials they combine venetoclax with more intensive chemotherapy show signs of good efficacy with good response rates, there are definitely signals of increased toxicity, hematologic toxicity, primarily. Which is not really unexpected with venetoclax knowing that it can cause significant lowering of white blood cells, platelets, and hemoglobin.

Then finally, there is a lot of interest in doing these types of combinations with venetoclax in different subsets of AML. And one subset of AML that has been very important recently is that of the IDH-mutated AML population of patients. IDH is a fairly common mutation that occurs in either in the form of IDH1 or IDH2, and there’s about a 15-20% incidence of IDH mutations in AML. Though we do have an inhibitor for both of these types of mutations, ivosidenib for IDH1 and enasidenib for IDH2, but there also appears to be a strong role for venetoclax plus azacitidine in IDH mutated AML. We saw from a series of patients presented by a physician at MD Anderson looking at outcomes with venetoclax plus azacitidine in IDH mutated AML. The response rates were very high when you give HMA plus venetoclax to these patients with IDH mutated AML. But, I think more importantly, is that there were what we call high intra-patient response rates when switching between venetoclax and HMA therapy with IDH inhibitor continued regimen. In other words, a patient would have a good chance of responding to the initial therapy, then, if or when that therapy stops working, having a good effect from the salvage therapy with the other regiment, So if you received initially azacitidine plus venetoclax, and then had a relapse, the IDH inhibitors worked well and vice-versa if have received an IDH inhibitor, then subsequently received HMA/venetoclax at a later time point, that also worked well.

So it’s encouraging to see that you can potentially sequence these drugs and get continued responses along the way that ultimately we think that will help survival and keep patients in a better state of health for longer.

So I just wanted to take a few minutes also and discuss some of the newer more novel therapies that are really hitting or approaching the landscape right now. One of these is called CC-486, also known as oral azacitidine or onureg, and this drug was shown in a recent literature to prolong overall survival in patients who are in first remission from their AML who had received induction chemotherapy. So this drug was used as maintenance therapy after a variable number of consolidation regimens and people who got this onureg or azacitidine drug as maintenance therapy, it resulted in longer survival compared to those who had received placebo. This was presented at last year’s ASH meeting, but this year’s ASH meeting provided an update, a very important update, showing that the overall survival advantage from this drug, this oral azacitidine drug, when used as maintenance was independent of whether a patient had measurable residual disease at the time that they went on to the maintenance therapy. In other words, whether you had MRD (measurable residual disease) or not at the time of the study entry, your responses were still more favorable, your outcomes were more favorable if you received this oral azacitidine drug. So this was FDA approved earlier this year for patients in the maintenance phase of therapy for AML who had got prior induction chemotherapy. 

And importantly, this drug was also shown to be able to convert about 25% of patients who were positive for measurable residual disease, to convert them from positive to negative. So even though they were in remission, they had measurable residual disease and this drug in about 25% of the cases converted them from positive to negative. So that’s a very important finding as well. 

Another important drug that I think you should keep your eye on is a drug called magrolimab. This is an antibody against a certain type of protein that is present on an immune system cell called the macrophage. And when this magrolimab drug is combined with azacitidine in a recent clinical trial, it was demonstrated very high response rates of over 65%, and in particular in patients with P53 mutation, which is a very bad mutation to have in most cancers including AML. In patients with this high-risk mutation, the combination magrolimab with azacitidine appears to be effective based on the early data that we have with high response rates.

And then finally, I just wanted to make mention of another important area in, not really just AML, but all cancer, and that’s outcomes disparities between different races and ethnic groups. And we saw a very important presentation at the plenary session this year where the authors reported outcomes amongst younger patients with AML who are African American compared with caucasion. And the data clearly indicated a worse overall survival amongst black patients compared to white patients under age 60. And this included patients who are enrolled in clinical trials. So that, it appeared that African American patients had a worse outcome than Causian patients with Acute Myeloid Leukemia. Highlighting the need to better understand various risk factors and other factors that play into these disparate outcomes between our black American population and our white American population, which I think could shed light on additional disease characteristics that many help everybody.

Katherine:

Dr. Lancet, thanks so much for joining us today

Dr. Lancet:

Thank you very much for having me. It was good to be with you.

Katherine:

And thank you to our audience, I’m Katherine Banwell.

Don’t miss an episode and subscribe to PEN’s Empowered! Podcast wherever podcasts are available.

What Standard Testing Follows a Myeloma Diagnosis?

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What Standard Testing Follows a Myeloma Diagnosis? from Patient Empowerment Network on Vimeo. 

What tests will you have following a myeloma diagnosis? Are there additional tests you should request? Dr. Joshua Richter provides an overview of key testing for myeloma and why each test is necessary.

Dr. Joshua Richter is director of Multiple Myeloma at the Blavatnik Family – Chelsea Medical Center at Mount Sinai. He also serves as Assistant Professor of Medicine in The Tisch Cancer Institute, Division of Hematology and Medical Oncology. Learn more about Dr. Richter, here.

See More From INSIST! Myeloma

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Is the COVID-19 Vaccine Safe for Myeloma Patients?

Transcript:

Katherine:

What standard testing follows a myeloma diagnosis?

Dr. Richter:

So, the standard testing that follows a myeloma diagnosis is multifaceted. So, the first one is blood work. And we draw a lot of blood tests to look at the bad protein that the cancer cells make. So, we send tests like a protein electrophoresis which tells us how high that bad protein is. We send immunofixation. That test tells us what type of bad protein it is. You’ll hear names like IgG kappa and IgA lambda.

These are the different types of bad proteins made by myeloma cells. Oftentimes, we’ll send urine tests to find out how much of that bad protein that was in the blood is coming out in the urine. We will, typically, do a bone marrow biopsy. It’s a test where we put a needle into the back of the hip bone to look at the marrow itself. And we’ll use that marrow to figure out how much myeloma there is, any other characteristics like the genetic changes in those cells.

The other big thing is imaging. So, the classic imaging that we do with myeloma is something called a skeletal survey. It’s, basically, a listing of X-rays from head to toe. But nowadays, we have newer techniques, things like whole body low-dose CAT scans, something called a PET-CT scan, and MRI scans. And your care team may have to figure out which one is right for you at what given time.

Katherine:

Mm-hmm. Are there additional tests that patients should ask for?

Dr. Richter:

Absolutely. One of the most important things from myeloma has to do with the genetic risk stratification.

So, for almost all cancers, the staging has a very big impact. And people will often think of cancer in stages I, II, III, and IV, and they’re managed very differently depending upon what stage it is. Myeloma has three stages, stage I, II, and III. But the most important thing is, actually, beyond the staging is what’s called the cytogenetics risk stratification. So, it’s really important when the bone marrow is sent to be sure that it is sent for, kind of, advanced techniques. Because you really want that snapshot of exactly what the genetic profile is, because that gives us information of A) how to treat, and B) prognostic, you know, who will tend to do better or worse based on this information. And even though that may not tell us which drugs to use, specifically, it may say, should we do something like a transplant or not? Should we consider a clinical trial early or not?

Katherine:

I see. How do test results affect treatment choices?

Dr. Richter:

So, test results can affect treatment choices in a number of ways. Probably, the most common one is thinking about the routine blood tests like your CBC or complete blood count and your chemistry, which looks at things like your kidney function. Some drugs tend to have more toxicity to the blood counts. So, if your blood counts are very low, we may choose drugs that don’t lower the blood counts very much.

Kidney function which we, usually, measure by something called the creatinine. Creatinine is made by the muscles and cleared out by the kidneys. So, if your kidneys aren’t working very well, you don’t pee out creatinine, and that creatinine level will rise in the blood. If your creatinine level is high, we may choose certain drugs that don’t affect the kidneys or not metabolized or broken down by the kidneys.

The genetic studies that we use – we’re not quite at this base yet where we can say, if you have this genetic abnormality in your myeloma, we should use this drug except there’s some really great data on the cutting edge about a drug called venetoclax.

Venetoclax is a pill that’s used to treat other diseases like lymphoma and leukemia. And it turns out that people who have what’s called a translocation (11:14) which means part of the 11th chromosome and part of the 14th chromosome in the cancer cells swap material.

Those people respond amazingly well to venetoclax. So, we’re starting to have what we would call precision medicine where we find your genetic abnormalities, not that you got from your parents or passed to your kids, but the genetics inside the tumor cells to tell us which treatments will work best for you.

Expert Advice for AML Patients When Making Treatment Choices

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Expert Advice for AML Patients When Making Treatment Choices from Patient Empowerment Network on Vimeo.

What are key factors to consider for acute myeloid leukemia (AML) patients when making treatment decisions? Dr. David Sallman reviews important considerations and their impact on treatment choices, and shares questions patients should ask their doctor to receive optimal care. 

Dr. David Sallman is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center where he specializes in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Learn more about Dr. Sallman, here.

See More From Engage AML

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How Molecular Testing Has Transformed AML Treatment Options

Transcript:

Katherine:

When making a treatment choice, what are three key considerations for AML patients?

Dr. Sallman:

Yeah, so I think the initial probably two main questions are is the patient fit or non-fit, and that’s really an evolving definition. I think historically, we had this magical age if you’re less than 60 or less than 65 years of age, but we’ve really gone past that significantly. So, does a patient have significant medical problems, decreased performance status that we would not think about intensive therapy is one of the main questions. I think what feeds into that. And the other big question is what is the underlying mutations that the patient has which really gives us a prognostic risk from a disease perspective.

With certain mutations and subgroups being much more sensitive to intensive chemotherapy and other groups really where that option is poor irrespective of age. So, I think the most important thing is how does the patient look, what is their fitness level, and what are the underlying cytogenetic and molecular changes that impact their disease.

I think third, of course, is really involving the patient in their preferences, because I think some of these can really be a decision between several options.

Katherine:

What’s the role of the patient in making treatment decisions?

Dr. Sallman:

Yeah, the patient has to be central. I’m really hoping that we’ve moved a long way from the paternalistic practices in the past.

I think there are still many instances where there’s sort of a clear best option from a medical perspective, but there’s a lot of social logistics. If you’re getting intensive therapy, as an example, you’re going to be in the hospital four to five weeks, what’s your support system? What financial, other impact factors, all of these things come into play. I think it’s a tough group. I think the patients that are, let’s say, 60 to 70, because responses are somewhat similar across non-intensive and intensive options, I think there’s the question of is the goal long-term, is the goal quality of life, and I think all of those really are impactful.

I think it can be very challenging to go through all of the specific numbers and how a patient comprehends that or not, but really trying to draw out is their goal long-term, is their goal quality of life, give them the pros and cons of the potential options in that setting, and then real-time discuss that as we go. I think when they have that buy-in from their goals, it’s important.

These are complicated regimens and patient compliance and follow-up and all that are really critical to the overall safety and good outcomes of these patients.

Katherine:

Are there questions that patients should ask in their proposed treatment plan?

Dr. Sallman:

Yeah. I think it’s always important to discuss what options. I think any time there’s a one-option, if there is a one-option, why? Maybe because standard of care in this group is so good that it’s not really reasonable to necessarily offer a main alternative regimen. I think it’s important to understand as much of the disease as possible. If you’re choosing this regimen, why are you doing it? I think asking about the mutations is important, although that’s a very complicated thing to explain. Some patients like it and some patients don’t, and I think you have to do that in your team-based relationship.

I think always asking about clinical trials is an important question to ask. Should they be getting a second opinion? These are overall very rare diseases, and we highly favor an initial consultation at an academic center that specializes in this. I’d say a majority of my patients are ultimately treated in the community. But especially given that the regimens are becoming much more complicated, the intensity of watching their counts, managing side effects, titrating medications, it’s really great to have a team-based model between academic and community centers and that can’t really ever happen if they never come to us. As much as possible for that to occur I think is important as well.

How Molecular Testing Has Transformed AML Treatment Options

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How Molecular Testing Has Transformed AML Treatment Options from Patient Empowerment Network on Vimeo.

How has molecular testing impacted approaches to acute myeloid leukemia (AML) therapy? Dr. David Sallman explains how molecular testing has transformed AML care, including a discussion of risk assessment and the role of next-generation sequencing (NGS) in tailoring care for each patient. 

Dr. David Sallman is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center where he specializes in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Learn more about Dr. Sallman, here.

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Transcript:

Katherine:

How has molecular testing changed the landscape of therapy for AML?

Dr. Sallman:

Yeah, it’s really transformed it, and it’s really a constantly evolving paradigm. We have updated classifications; most people utilizing the ELN system.

So, based on both cytogenetic and molecular factors, you can ultimately go into good risk, intermediate risk, adverse risk. In general, for fit patients for good risk, we focus on curative intent, ideally with chemotherapy alone. For intermediate and adverse, typically we’re incorporating allogeneic stem cell transplant. So, that’s one of the main things that really guides treatment really from the beginning and throughout.

Then, I think really where it’s evolving is personalized therapy. So, it’s really not a one-size-fits-all treatment paradigm, it’s you have mutation A, B, you’re this age, this fitness, and we put all those things together to ideally come up with the best treatment plan for the patient.

Katherine:

Is molecular testing standard following an AML diagnosis or is this something that patients should ask for?

Dr. Sallman:

It definitely should be standard and I think the challenge is when you say the word “molecular,” it means lots of things to different people. I think in the community, as targeted medications were first approved, so this was with FLT3 inhibitors, subsequently IDH1 and IDH2 inhibitors, I think people are realizing yes, we have to send these sequencing panels, but there’s a potpourri of choices from a lot of different commercial vendors.

Really the key and one of the main messages we try to get across is you really have to assess for both FLT3 as well as really a comprehensive next-gen sequencing panel in order to cover all of the relevant genes at diagnosis and likely at other time points such as relapsed or refractory disease.

So, there’s no question, it’s standard, although unfortunately, it’s still not uncommon where the comprehensive panels are not sent and you’re left with somewhat not a complete picture for your patients. Since we’re personalizing everything, it’s really quite critical to have these data.

Katherine:

Yeah. How does inhibitor therapy work to treat AML?

Dr. Sallman:

So, you have a gene that turns on and turns off as we go, but with the mutation, it’s basically turned on all the time. Then, you can have targeted pills that basically turn it off. Most commonly this is done, there’s the active

or energy site for these different genes, and so these therapies can really specifically block that. I wouldn’t say that’s the only mechanism. There are IDH1 and IDH2 inhibitors and they’re very specific for those mutations. Each mutation may have a little bit different end biology. In general, you have mutation A, and we’re going to turn it off with drug that inhibits A.

Treatment Advances for Aging AML Patients

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Treatment Advances for Aging AML Patients from Patient Empowerment Network on Vimeo.

What are the latest acute myeloid leukemia (AML) treatment advances for elderly patients? Dr. David Sallman shares details about new therapies that he’s excited about and their impact on care for all AML patient groups.

Dr. David Sallman is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center where he specializes in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Learn more about Dr. Sallman, here.

See More From Engage AML

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How Molecular Testing Has Transformed AML Treatment Options

Transcript:

Katherine:

Okay. When it comes to AML research and emerging treatment options, what specifically are you excited about?

Dr. Sallman:

Yeah. So, I think probably the most exciting changes have really been in the overall elderly AML setting, although I think are really broadly impactful across patients.

So, the standard has been hypomethylating agents for a long time. This paradigm has recently changed with the FDA approval and now full approval of venetoclax in combination with hypomethylating agents, but we’re still talking about immediate overall survival of 14 months in the Phase III setting.

There are lots of exciting drugs, and I think this is really where the spectrum of myelodysplastic syndrome and acute myeloid leukemia comes into play.

So, I really think in elderly AML, we’re moving towards more triplet type combinations to really ideally move the field forward. That adds levels of complexity, toxicity from additional therapies, but we’re really hoping to truly move that survival curve even more.

There’s a lot of HMA, doublet, triplet combinations that are exciting and I think that’s really where the field is going.

I think at the same time in the failure setting, particularly, let’s say, in the HMA venetoclax failure setting, there’s really a lack of almost any effective therapies. We’re really hoping that novel cellular and immunotherapies will hold significant promise in this group. There are numerous trials that are being considered in this space, but I’m hopeful for it.

How to Play an Active Role in Your CLL Treatment Decisions

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How to Play an Active Role in Your CLL Treatment Decisions from Patient Empowerment Network on Vimeo.

How can you partner with your healthcare team to feel confident in your CLL decisions? In this webinar replay, Dr. Matthew Davids discusses CLL treatment approaches, developing research and tools for partnering with your healthcare team. Dr. Matthew Davids is the Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute.

Download Guide

See More from Engage CLL

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Which CLL Treatment Approach Could be Right for You?

Transcript:

Katherine:                  

Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today we’re going to explore the factors that guide CLL treatment decisions, including your role in making those decisions. Before we meet our guest, let’s review a few important details. The reminder email you received about this program contains a link to program materials. If you haven’t already, click that link to access information to follow along during the webinar. And at the end of this program, you will receive a link to a program survey. This will allow you to provide feedback about your experience today, and it will help us plan future webinars.

Finally, before we get into the discussion, please remember that this is not a substitute for seeking medical advice. Refer to your own healthcare team. All right, let’s meet our guest today. Joining me is Dr. Matthew Davids. Dr. Davids, would you please introduce yourself?

Dr. Davids:                  

Hi, Katherine. Thanks so much for having me. It’s great to be with everyone today. I’m Matt Davids. I’m a CLL-focused physician based at Dana Farber Cancer Institute in Boston, and I’m also an associate professor of medicine at Harvard Medical School. And I get to wear many hats here. First and foremost, I take care of patients, particularly patients with CLL, but I also have some administrative roles. I direct our clinical research program in the lymphoma division. I also run a research laboratory focused on CLL and other lymphoid cancers, and I run about a dozen clinical trials mostly focused on developing new treatment options for patients with CLL.

Katherine:                  

Wow. Sounds like you’re a busy guy. I’m glad you have the time to join us today.

Dr. Davids:                  

My pleasure.

Katherine:                  

Let’s start with a question that’s on the mind of many of our audience members. Is the COVID-19 vaccine safe for CLL patients?

Dr. Davids:                 

Very timely question. The simple answer is yes. There are now actually three different vaccines that have been granted emergency use authorization by the FDA.

And I would say that so far, we’ve seen clinical trial evidence suggesting these are very safe vaccines in the general population.

Our own experience with our own CLL patients so far has also suggested safety, so I think it’s very important that our CLL patients get vaccinated as soon as they can. I think the bigger concern more than safety is on the efficacy side of the vaccine, meaning how effective are these vaccines going to be for CLL patients? That’s not something that we know yet from the larger clinical trials that have been done. So, those numbers you see quoted, 95 percent protective, that’s in the general populations.

We do worry a bit based on our experience with other vaccines in CLL patients that they may not be quite as effective, but we don’t know that yet. Fortunately, that’s something that we’re studying now, both at our center and in some nationwide efforts, to look for example at the antibody production that CLL patients can make before and after vaccination. I’m hopeful that over the next few months we’ll start to learn about how effective these vaccines are specifically for CLL patients.

We certainly expect they will have some benefit, so that’s why we recommend vaccination for all of our CLL patients. But once patients are vaccinated, it doesn’t give them a free pass to then take their masks off and go back to normal life. Particularly CLL patients I think need to be careful even after vaccination to continue to do social distancing, hand hygiene, and all these things.

Katherine:                  

Is there one type of vaccine that’s more suited for CLL patients?

Dr. Davids:                 

Nope. As far as we can tell, all three of the approved vaccines so far are safe and should have some good effects for CLL patients.

There’s no benefit of one versus the others, so the best one to get is the one that’s in your muscle and injected. Whatever you can get access to, that’s the best one for you.

Katherine:                  

Dr. Davids, have there been any recent developments in CLL treatment and research that patients should know about?

Dr. Davids:                 

Yeah. We could spend a few hours on this, but I’ll try to summarize it. There’s a lot of exciting developments in the field. and I think we’re going to get into some of the specific treatments in a few minutes, but I would say at a high level obviously, over the last decade the entire field of CLL treatment has been transformed. Whereas we only had chemotherapy-based approaches before, now we have a whole number of different drugs that we call novel agents. And the reason why they’re novel is that they target the CLL cells, but they spare the other cells in the body, so there’s less collateral damage there. What that means is that they have fewer side effects, and they’re more effective, so it’s really a win-win situation for patients.

There’s kind of been two main approaches for this.

One is to start a novel agent drug and to continue it for as long as it’s helping, which fortunately for most patients is a long time, many years. And then, a newer approach is actually to do what’s called time-limited therapy where you start usually at least a couple of these different novel drugs together but hopefully achieve what we call a very deep remission, meaning excellent shrinkage of lymph nodes and improvement of blood counts and bone marrow disease. And by getting these very deep remissions the idea is we can do a finite period of treatment, whether it’s one year or two years, it kind of depends on the regimen. And then, stop therapy and hope that patients can then enjoy many years of remission while off therapy, which can be nice in terms of reducing side effects and costs and all these other things.

So, those are the biggest developments in the field right now, the continuous novel agent therapy and time-limited novel agent therapy. And a lot of the clinical trials that are getting off the ground now are starting to compare these two strategies to figure out really what’s the optimal way to treat CLL patients.

Katherine:                  

How can patients stay up-do-date on developments like these?

Dr. Davids:                 

It’s definitely challenging. It’s challenging even for us who are in the field to keep up with things on the academic side. I think for patients, seeking out patient-friendly sources of information on the web are helpful, but sometimes it can be hard to know what’s reliable information on the web. So websites like this and programs like this I think can be very helpful. Another resource that a lot of my patients find helpful is the CLL Society, so www.cllsociety.org. Brian Koffman really curates a lot of the new developments in the field on that website nicely. He interviews a lot of different CLL experts in this short format that can be very digestible for patients. Patient Power is another great website. So, there are a bunch of them out there, and I think those can be a great resource for our patients.

Katherine:                  

When a person is diagnosed with CLL they have a whole healthcare team. Who’s typically on that team?

Dr. Davids:                 

It’s definitely a multidisciplinary team.

Usually there’s an oncologist-hematologist who’s leading the team as a physician, but there’s a very large team of other people who are involved, whether it’s an advanced practice person such as a nurse practitioner or a physician’s assistant. They’re often very closely involved with the day-to-day patient care. There’s nurse navigators in some places that can help with getting access to these novel agents and with looking into clinical trial opportunities. There’s pharmacy folks who are very helpful sometimes in checking in on side effects, and advising on dosing, and so forth.

That’s more on the provider side of things. But, of course, the care team really includes the caregivers for the patient, whether it’s family members or friends, who are really a crucial part of this. The field is very complicated, and one of the challenges with COVID recently is that I’ve always invited family members and friends to come to visits with patients, because I do think it’s helpful to have many people listening. And that’s been hard because we’ve had to restrict visitors usually to either no visitors or one visitor because of COVID precautions.

Even if that’s the case, you can still have people dial in by phone or use technologies like FaceTime to try to have them there with you, because I think having that extra set of ears can be helpful as you hear all this information coming at you from your oncologist.

Katherine:                  

Yeah, absolutely. So, it really does sound like it’s a whole team approach. We have a question from the audience. Linda writes, “I’ve heard that CLL doesn’t need to be treated right away. Is that true?” 

Dr. Davids:                 

That is true for the majority of CLL patients, and it’s actually a very counterintuitive thing. We’re conditioned that if you have cancer that it’s important to be proactive and get rid of it as quickly as possible, the sooner the better, and that is actually not the case in CLL. And we didn’t just take a guess that that’s the best approach. This is actually something that’s been studied in clinical trials. There were several clinical trials launched in the ‘70s and ‘80s looking at an early intervention strategy using a chemotherapy-based approach to see if treating at the time of diagnosis would be better than waiting until patients developed more significant symptoms.

And all of those studies did not show a benefit to early intervention.

Now, more recently those studies have been challenged as somewhat out of date, which is a fair criticism because they used an older chemotherapy drug. And so, there is a newer study now going on in Europe that is looking at early intervention with the drug ibrutinib, which is one of our novel agents for CLL, looking to see if early intervention with ibrutinib, particularly for patients who have a higher risk form of CLL, may be beneficial.

But we have seen some data now already presented from this study that do not show any improvement in how long the patients live by treating with ibrutinib early, and we do see some of the typical side effects that we’re accustomed to seeing with ibrutinib. So, even with the newer data that we’re seeing, we still do not recommend early intervention for patients with CLL.

Katherine:                  

I’ve heard this term “watch and wait.” What does that mean?

Dr. Davids:                 

Yeah, it’s not the best term because it’s very passive. That refers to this observation strategy. I like to think of it more as “active surveillance.” It seems more proactive because you’re doing something about it.

You’re really checking the blood counts, you’re getting your physical exam, you’re checking in on symptoms, these sorts of things, and really keeping a close eye on the disease. And that’s the approach that we like to take with our patients to really keep them engaged, making sure they’re staying up-to-date on their screenings for other cancers, making sure they’re getting vaccinations, these sorts of things are all the things we do with active surveillance.

Katherine:                  

How is someone monitored during this watch-and-wait period?

Dr. Davids:                 

It varies depending on individual patients. We’ve alluded to the fact that there’s different genetic subgroups of CLL already, so there are some patients that have higher-risk disease. The example of that usually is deletion 17p that people may have heard of on the FISH test. For those patients I usually am seeing them every three months or so, physical exam, checking on their history, checking their bloodwork. But there’s quite a few CLL patients who have lower-risk disease. If they have for example mutated IGHV, if they do not have the 17p for example, those patients may be able to be seen once every six months or so with a similar setup.

 I don’t routinely get CAT scans on a regular basis for most patients. Most patients don’t need bone marrow biopsy tests unless they’re starting treatment. So, it’s mostly it’s exam, talking to patients, and checking the bloodwork.

Katherine:                  

Okay. So, how does CLL progress? When do you know when it’s time to treat?

Dr. Davids:                 

The stages of CLL involve the progression of the disease. When we first meet patients, often they only have cells circulating in the blood, and that’s called stage 0 disease. It’s one of the few cancers where there’s actually a Stage 0 before even Stage I, and the reason for that is that many patients can go for years on Stage 0 disease. But as the burden of the CLL cells begin to accumulate in the body they can start to collect in their lymph nodes, and the lymph nodes can start to swell up whether it’s in the neck or the armpits or elsewhere. That’s stage I disease.

They can accumulate in the spleen, which is an organ in the abdomen. It’s kind of a big filter for your bloodstream, and as the filter traps more of these lymphocytes the spleen can slowly enlarge over time. That’s stage II disease.

And then finally, the CLL cells can get into the bone marrow, which is like the factory for making your blood cells. And if the factory floor gets all gummed up with CLL cells it can’t make the normal red cells, that’s called anemia. Or it can’t make the normal platelet cells, that’s called thrombocytopenia. And when we start to see those more advanced stages III and IV of CLL, that usually does require treatment. And what the treatment does is it clears out the factory floor and it allows for the normal machinery to make the normal blood cells again. So, that’s one of the more common reasons why treatment is needed is due to anemia and low platelets. Second reason can be if the lymph nodes or spleen get so bulky that they’re uncomfortable or threatening organs internally. We want to treat before that becomes a real threat.

And then, the third thing that usually happens as the disease progresses, patients can develop some symptoms, what we call constitutional symptoms. These can be things like unintentional weight loss, drenching night sweats that are happening on a consistent basis, and those sorts of things. So, if that’s happening at the same time as these other factors are progressing, those would be reasons to treat.

And notice that one thing I did not say is the white blood cell count itself.

That’s a common misconception. Some people think that as the white blood cell count goes higher – and people use all different thresholds, 100, 200 – that by crossing that threshold you need to start treatment. And in fact, that’s not the case. We have many patients whose white blood cell count can get very high but then it can kind of level off and plateau for a period of several years, and as long as they don’t meet those other treatment indications, they don’t need to be treated just based on the white count alone.

Katherine:                  

Hmm, okay. Well, once it’s time to treat, of course then it’s time to think about treatment options. Let’s walk through the types of treatments that are used today to treat CLL.

Dr. Davids:                 

As I alluded to before, we historically have had chemotherapy-based approaches to treat CLL. And that was an effective way to temporarily put the disease into remission, but it had a lot of side effects and inevitably the CLL would come back. And the challenge particularly with chemotherapy-based approaches it that when the CLL does come back after chemotherapy, it tends to behave more aggressively and be harder to treat.

So, there have been quite a few studies over the last few years trying to figure out ways that we can avoid using chemotherapy as the first treatment, and this can involve treatments such as monoclonal antibodies. People may have heard of rituximab or a newer drug, obinutuzumab. There are the inhibitors of the B-cell receptor pathway, and this is for example ibrutinib, which targets a protein called BTK, also a newer one called acalabrutinib, which targets BTK. And then, I mentioned at the beginning these fixed-duration therapies that stop after a period of time. Many of those are based on a newer oral drug called venetoclax, which when we give it as a first therapy, we give in combination with that antibody obinutuzumab.

So, a bit of an alphabet soup. I know it gets confusing with all the different treatments, but the good news for CLL patients is, 1.) we have a lot of options, which is great, 2.) we don’t necessarily need to use chemotherapy anymore, and in fact I use it pretty rarely these days. One situation where I do still consider chemotherapy is for younger patients – which in the CLL world is sort of under age 60 or so – if they have very favorable biology to the disease, in particular this mutated IGHV.

That’s a scenario where the older chemotherapy regimen, FCR, can be very effective. It’s a six-month treatment, and we have patients with those molecular characteristics who are now 12, almost 15 years out from their initial six months, and they’re still in a complete remission. So, many of those patients have been functionally cured of their CLL from the six months of treatment. But again, there are some risks to that approach. We worry about other cancers that may be more likely after receiving FCR. We worry about infections, and particularly in the COVID situation, we worry about COVID infection in patients on chemotherapy.

So, it’s been pretty rare that I’ve been using that approach these days. I’ve been opting more for the novel agent-based approaches. So, often now the conversation as an initial therapy comes down to, “Do you prefer more of a continuous treatment strategy with a BTK inhibitor drug like ibrutinib or acalabrutinib, or do you like the idea of a time-limited therapy with one year of venetoclax in combination with obinutuzumab?” And I would say there’s pros and cons to both approaches, and we don’t know which one is the optimal one for CLL patients to start with, but probably I think most patients at some point in their lifetime are going to need one therapy or the other.

So, maybe in the end it doesn’t matter too much which one you start with if you’re going to get both eventually anyway. But we don’t know that yet.

Katherine:                  

Right. Where do clinical trials fit in with the treatment approaches?

Dr. Davids:                 

So, clinical trials are really how we’ve made all these advances in CLL over the last decade. It’s how we learn about new treatments. It’s how we learn about how to optimize the treatments that we have. I think sometimes patients have a misconception that clinical trials are a last resort, the idea that you’ve exhausted all the standard options and then you go to a clinical trial as your last hope. But I actually like to kind of turn that on its head and say that clinical trials are actually the first resort, the first best option for patients. Whenever patients can get access to a clinical trial at any stage of their disease, I would really encourage them to consider it.

We have quite a few clinical trials now in the frontline setting, meaning as an initial treatment for CLL, including some that are in development and will open soon. And these are the studies that are going to really help us define what the optimal regimens are. What’s the optimal sequence of these different novel agents?

And in CLL, really, we’re at a point where the research on the disease is so mature that when you’re in a clinical trial you’re either going to be on one regimen that you know you’re getting and you know it’s going to be an effective regimen, or you might be in a comparative trial where you could be randomized to one of two or three different regiments, but you know that each one of those regimens is one that we think is a great regimen. We just don’t know which one is optimal for individual patients. So, this is not a situation where there’s placebo-controlled trials where you don’t know if you’re going to get an active treatment or not. CLL is an area where we design our clinical trials so that all patients are going to be benefiting from cutting-edge approaches.

And so, not all patients have access to trials, and that’s okay. Again, we’re fortunate that we have many good options that can be given locally, but I do encourage patients even if they’re only able to travel to a CLL specialist once to have an initial consultation to think about doing that to get a CLL specialist on your team, so to speak. That way they can identify clinical trial options that may be a good fit, and even if not, they can advise on what the optimal treatment options are to receive locally with your own oncologist.

Katherine:                  

How do patients find out about these clinical trials?

Dr. Davids:                 

I do think the best way is through a CLL specialist because certainly they would have a great pulse on the trials, they have available at their own center. They should also have a sense for what trials are available maybe at other centers. Some of that can also be, there’s a great resource through The Leukemia & Lymphoma Society where they can help navigate patients toward specific trials that may be applicable to them.

There’s also a website called clinicaltrials.gov. It can be a little challenging if you’re not familiar with it to navigate the site, but it is actually pretty straightforward. You can put in the disease and look at different options for trials based on different drugs, for example. They’ll list the eligibility criteria for the trial. That’s often I find a way that patients can begin to identify whether they may be a candidate. You can’t tell from the website whether you’re definitely a candidate or not. You really need to partner with an investigator who’s on the trial to learn that, but it certainly can be a good starting point to figure out what’s out there.

Katherine:                  

With CLL, what are the goals of treatment?

Dr. Davids:                 

I like to say to patients, “The goals are to make you live longer and live better.” You want to obviously have treatments that prolong life, but you also want to have treatments that are helping with symptoms, and giving patients more energy, and making them feel better, and protecting them from some of the risks of the disease. And so, I think the goals do vary a bit based on the stage of life that patients are at.

I see a lot of patients in their 70s and 80s, and in those patient’s symptom control, having the disease be in a good remission, allowing them to live their life is a good goal. I sometimes see patients in their 40s and 50s, and some of those patients want to be a bit more aggressive and try to do a strategy that will get them a very long-term remission, and even potentially explore potentially curative strategies.

If I have a higher-risk patient with deletion 17p who’s young and fit, and they’ve already had some of the novel treatments, that’s where we start thinking about clinical trials of some of the cellular therapies like CAR-T cells that people may have heard of where you use the T cells from the patient to try to use that as a therapy to kill off the disease. Or even a bone marrow transplant is something that we have used historically in CLL. We don’t use it as often now, but for younger patients with high-risk disease it’s still a consideration to try to achieve a cure of the CLL even though the risks of that are significant.

It sounds like there are several factors to weigh then in making this decision. Lately we’ve been hearing the term “shared decision-making,” which basically means that patients and clinicians collaborate to make healthcare decisions.

And it can help patients take a more active role in their care. What are your thoughts, Dr. Davids, on how best to make this process work?

Dr. Davids:                 

Yeah, I fully support that model. I think for most patients it’s very helpful to be an important decision maker. Really the patient is the ultimate decision maker to say what they want for their own treatment. And sometimes it’s hard for me to predict what a patient will want for themselves, so I see my role for most patients as providing the information that they need to make the best decision possible for themselves.

I do try to steer patients a bit in the directions that I think they should be thinking. I’m not going to necessarily present a laundry list of things to patients. I’m going to try to narrow it down to what I think are the most reasonable choices for a patient to make.

I feel that’s part of my job. I do still have patients who just say, “Just tell me what to do,” and I respect that, too. Not all patients want to be part of shared decision making, and they just want me to decide, and that’s fine. But I do find that most patients like the idea of having a voice and being the one to decide, and that way I can help to guide them, but ultimately, it’s up to them.

Katherine:                  

Well, speaking of patients having a voice, are there questions that patients should consider asking when they’re thinking about a proposed treatment plan?

Dr. Davids:                 

Yeah. I think some of the key ones revolve around basic stuff, but sometimes it’s hard to think of it in the moment. But thinking about, what are the risks of this therapy? What are the specific side effects that are most common? When you look at a package insert or you look at a clinical trial consent form, you’re going to see 100 different side effects listed. I always promise patients, “You won’t have every single side effect that’s listed here, but you may have a couple of them.” And again, my role often is to identify which are the more common side effects that we see and how can those be managed?

And then, I think often you’re just asking simply about what are the potential benefits of this therapy? What are the odds that I’m going to get into remission? How long is this remission likely to last?

And then, something that is often challenging for patients to think about – it can be challenging for me as well – is to think about what’s the next step? So, I think a good question to ask is, “If I choose Therapy A, what happens if I need therapy again in a few years? What are the options at that point?” because we’ve been talking so far mostly about what we call frontline therapy, making that initial choice of treatment. But then, once you get into what we call the relapse setting, a lot of the decision of what to receive at that point depends on what you got as the first therapy. And so, trying to think at least one step ahead as to what the next options are I think can be helpful, certainly for the physicians but also for the patients.

Katherine:                  

Do you have any advice to help patients speak up when they’re feeling like their voice isn’t being heard?

Dr. Davids:                 

That’s always a challenging situation, but I encourage patients not to be shy about asking questions.

There’s often an imbalance in terms of the information where the oncologist may know more than the patient about a particular condition. And so, I think reading up and trying to educate yourself as much as you can. Whenever possible, including a family member or friend as part of the visit to also help advocate for you. And then, if you’re not being heard the way that you think you should be, thinking about seeking out another provider who may be able to listen more.

And sometimes that can be again helpful to have a touchpoint with a CLL specialist who may be able to reinforce some of what you’re thinking. If what you’re reading online or seeing online is different from what your oncologist is telling you, that may be a sign that it’s good to get a second opinion and just make sure you’re on the right track.

Katherine:                  

All really helpful advice, Dr. Davids. Before we end the program, what are your thoughts about the future of CLL treatment and research?

Dr. Davids:                 

I’m very optimistic about where things are right now. We’ve gotten to this point where we have so many different effective options, so it’s fun for us to now design this next wave of clinical trials to really try to optimize the outcomes for patients.

One area I’m particularly interested in is a concept called MRD, which we haven’t talked about yet, but minimal residual disease is a way to look even at a molecular level for tiny amounts of CLL that may be left behind after treatments. And so, one of the things I’m particularly excited about is the idea eventually of using what we call MRD-guided therapy.

So, we talked before about continuous treatment. We talked about what we call fixed-duration treatment where everyone gets a year or everyone gets two years. MRD-guided therapy would actually allow us to vary the length of therapy depending on how a particular patient responds. So, some patients may need one year of a particular combination, but other patients may need two years. This could be a way to really individualize therapy for particular patients. It’s also a way to monitor patients who are in remission after they’ve stopped therapy.

And so, there’s another wave of trials looking at, should we be intervening early when patients develop recurrence of their MRD rather than waiting until they’re having progression of the disease? There’s still a lot of unanswered questions about these sorts of approaches, but I think it’s going to help us get even better at treating CLL.

All of this is contingent though upon the fact that patients continue to be interested in clinical trials and enrolling in trials so that we can really push the boundaries and learn even more about the disease. So, again, if no other message comes through, it’s really to think about clinical trials as a way to continue to improve outcomes for all patients with CLL. I think it’s a great situation where both the individual patient who’s participating in the trial can stand to benefit, but then also you can really be giving back and helping others.

Katherine:                  

Dr. Davids, thank you so much for taking the time to join us today.

Dr. Davids:                 

It’s my pleasure. Thanks so much.

And thank you to all of our partners. If you would like to watch this webinar again, there will be a replay available soon. You’ll receive an email when it’s ready. You’ll receive an email when it’s ready. Don’t forget to take the survey immed – don’t forget to take the survey immediately following this webinar. It will help us as we plan programs for the future. To learn more about CLL and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us.

What AML Patients Should Know About the COVID-19 Vaccines

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What AML Patients Should Know About the COVID-19 Vaccines from Patient Empowerment Network on Vimeo.

What are some key points for acute myeloid leukemia (AML) patients to understand about the COVID-19 vaccines? Dr. David Sallman shares advice for patients who are considering the COVID-19 vaccine.

Dr. David Sallman is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center where he specializes in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Learn more about Dr. Sallman, here.

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Transcript:

Katherine:

Are the COVID-19 vaccines safe for AML patients, and how does the vaccine affect treatment, if at all?

Dr. Sallman:

Yeah, I think that’s a great question. I think it’s really a rapidly evolving day-by-day update. For example, at our center, we vaccinated a high number of patients and we’re actually in a study trying to understand what their antibody production. So, I think the question is less ‘is it safe or not safe,’ but more is it as effective or worthwhile based on patients that have low blood counts.

I think, in general, if a patient is in remission, either post-therapy or on maintenance-type therapy that has a relatively preserved white count and is it’s very reasonable to utilize it, I think we still have the caveat of is it as effective, of course we don’t know that clearly since all the large trials, these patients weren’t really included. But in general, if you’re not severely leukopenic, we are vaccinating a high percentage of patients that we’re monitoring closely, but anecdotally, we’ve not had significant different adverse events from our perspective.

AML Research Updates: News From ASH 2020

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AML Research Updates: News from ASH 2020 from Patient Empowerment Network on Vimeo.

AML expert Dr. Jeffrey Lancet shares the latest news from the 2020 American Society of Hematology (ASH) annual meeting. Dr. Lancet sheds light on headlines from the meeting including FLT3 inhibitor research, combination therapies with venetoclax, a promising inhibitor therapy, and shares his optimism about the future of AML treatment.

Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

Download Program Resource Guide

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Transcript:

Katherine:      

Hello, and welcome. I’m Katherine Banwell. Today we’ll discuss the latest news from ASH 2020 and how AML patients can advocate for personalized care. Joining me is Dr. Jeffrey Lancet. Welcome. Would you please introduce yourself?

Dr. Lancet:                   

Hi, sure. My name is Dr. Jeff Lancet. I’m at the Moffitt Cancer Center in Tampa, Florida, where I am the Chair of the Malignant Hematology Department. We spend a lot of time treating patients and conducting clinical trials of Acute Myelogenous Leukemia.

Katherine:                   

Okay. Thank you. Dr. Lancet, the American Society of Hematology Annual Meeting just closed. What are the AML headlines from this year’s meeting?

Dr. Lancet:                   

Yeah, so as usual, AML was a very busy area for clinical presentations this year at the ASH meeting focusing largely on novel and targeted therapies.

I don’t believe that there were many practice changing developments per se, but rather discussions about many promising therapeutic strategies that are still under development and moving forward rapidly largely in the areas of targeted therapy, low intensity therapy, measurable residual disease and things of that nature.

Katherine:                   

What does this research news mean for patients?

Dr. Lancet:                   

Well, I think that there’s a lot to be encouraged about and maybe I’ll take the time to review some of the highlights in what was presented with respect to some of the novel therapeutic approaches that many of our patients can look forward to receiving in the not too distant future.

So, we often talk about you know, targeted therapies and, of course, one of the major targets over the years has been that of mutated FLT3 which is one of the most common mutations in AML.

And at this meeting we saw several presentations on clinical trials resolved to utilizing inhibitors of FLT3, with some emphasis on the most recently approved second generation drug called gilteritinib.

There were I thought three major presentations focusing on gilteritinib and one was an update on a randomized Phase III trial comparing gilteritinib plus azacitidine versus azacitidine alone in newly diagnosed unfit for induction chemotherapy patients with FLT3 mutations, preliminarily showing good tolerability and high composite complete response rates in the combination on.

There was another trial of gilteritinib plus venetoclax in relapsed and refractory FLT3 mutated AML.

And what was interesting was that a very high percentage of patients achieved response with this combination of gilteritinib plus venetoclax, many of whom were heavily pretreated previously and many of whom had also gotten prior FLT3 inhibitor therapy during an early stage of the disease. So, the combination of gilteritinib and venetoclax and this more refractive study, it was encouraging to see these promising responses.

And then we saw some data reporting the effects of gilteritinib in combination with more traditional chemotherapy induction with a couple of studies demonstrating both a high complete response rates as well as high rates of mutation clearance of the FLT3 mutation.

So, those were very encouraging data that were presented with respect to the FLT3 mutated AML population.      

So, another very important drug that reached the marketplace for AML recently is a drug called venetoclax, which is an inhibitor of a protein called BCL2.

And this drug was recently FDA approved for use in combination with low intensity chemotherapy drugs such as azacitidine or decitabine.

And it seems as though the combination of venetoclax plus one of these hypomethylating agent drugs, azacitidine or decitabine has resulted in very, very strong efficacy signals as recently published in a New England Journal of Medicine paper that reported on the results of the Phase III trial of venetoclax plus azacitidine.

So, that has now become standard of care for older less fit adults with newly diagnosed AML; the combination of venetoclax plus a hypomethylating agent such as azacitidine.

And naturally, there’s been interest in really kind of taking it several steps further to advance the role of these combinations and to also look at additional drugs in combination with venetoclax plus hypomethylating agent therapy.

So, we saw some of that at the ASH meeting this year. One approach would be to take venetoclax and then to combine it with more intensive chemotherapy for perhaps more fit patients or younger patients that could undergo a more intensive program.

So, we saw presentations of venetoclax being combined with a drug called CPX-351, which is a novel liposome formulation of two common chemotherapy drugs that had been approved a few years ago for secondary AML. And we also saw a combination strategy with venetoclax, and a regimen known as FLAG-IDA, which is a commonly used induction regimen in acute myeloid leukemia.

And I think it’s important to recognize that although these trials that combine the venetoclax with more intensive chemotherapy showed signs of good efficacy with good response rates, there were definitely signals of increased toxicity, hematologic toxicity primarily, which is not completely unexpected with venetoclax knowing that it can cause significant lowering of white blood cells and platelets and hemoglobin.

And then finally, there is a lot of interest in, you know, doing these types of combinations with venetoclax in different subsets of AML and one subset of AML that has been very important recently is that of the IDH mutated AML population of patients.

IDH is a fairly common mutation that occurs either in the Isoform of IDH1 or IDH2 and there’s about a 15 to 20 percent incidence of IDH mutations in AML.

Now we do have an inhibitor for both of these types of mutations: ivosidenib for IDH1 and enasidenib for IDH2, but there also appears to be a strong role for venetoclax plus azacitidine in IDH mutated AML.

We saw from a series of patients presented by a physician at MD Anderson looking at outcomes with venetoclax plus azacitidine in IDH mutated AML. And the response rates were very high when you give HMA plus venetoclax to these patients with IDH mutated AML.

But I think more importantly was that there were what we call high intro patient response rates when switching between venetoclax and HMA therapy with an IDH inhibitor containing regimen.

In other words, a patient would have a good chance of responding to the initial therapy and then if or when that therapy stops working, having a good effect from a salvage therapy with the other regimen. So, when you see initially azacitidine plus venetoclax and then had a relapse, the IDH inhibitors worked well and vice versa if you had received an IDH inhibitor and then subsequently received HMA-venetoclax at a later time point that also worked well.

So, it’s encouraging to see that you can potentially sequence these drugs and get continued responses along the way and ultimately we think will help a survivor and keep patients in a better state of health even longer.               

So, I just wanted to take a few minutes also and discuss some of the newer more novel therapies that are really hitting or approaching the landscape right now. One of these is called CC486, also known as oral azacitidine or ONUREG. And this drug was shown in recent literature to prolong overall survival in patients who are in first remission from their AML who had received induction chemotherapy.

So, this drug was used as maintenance therapy after a variable number of consolidation regimens. And people who got this ONUREG or oral azacitidine drug as maintenance therapy, it resulted in longer survival compared to those who had received placebo.

And this was presented at last year’s ASH meeting, but this year’s ASH meeting provided an update, a very important update, showing that the overall survival advantage from this drug, this oral azacitidine drug, when used as maintenance was independent of whether a patient had measurable residual disease at the time that they went onto the maintenance therapy.

In other words, whether you had MRD, measurable residual disease or not at the time of the study entry, your responses were still more favorable, your outcomes were more favorable, if you received this oral azacitidine drug.

So, this was FDA approved earlier this year for patients in the maintenance phase of therapy for AML who had gotten prior reduction chemotherapy.

And importantly, this drug was also shown to be able to convert about 25% of patients who were positive for measurable residual disease; convert them from positive to negative. So, even though they were in remission, they had measurable residual disease and this drug in about 25 percent of the cases converted that from positive to negative. So, that’s a very important finding as well.

Another important drug that I think you should keep your eye on is a drug called magrolimab. This is an antibody against a certain type of protein that is present on the immune system cell called the macrophage, and when this magrolimab drug was combined with azacitidine in a recent clinical trial, it was demonstrated very high response rates of over 65 percent.

And, in particular, in patients with P53 mutations, which is a very bad mutation to have in most cancers, including AML, in patients with this high-risk mutation, the combination of magrolimab with azacitidine appears to be effective based upon the early data that we have with high response rates.

And then finally, I just wanted to make mention of another important area in, not really just AML, but in all cancer and that’s  outcomes disparities between different races and ethnic groups. And we saw a very important presentation at the plenary session this year where the authors reported outcomes amongst younger patients with AML who were African American compared with Caucasian.

And the data clearly indicated a worse overall survival amongst Black patients compared with white patients under age 60. And this included patients who were enrolled in clinical trials. So, that it appeared that African American patients have a worse outcome than Caucasian patients with acute myeloid leukemia highlighting the need to better understand various risk factors and other factors that play into these disparate outcomes between our Black American population and a white American population, which I think could shed light on additional disease characteristics that may help everybody as well.

 

Understanding AML Induction and Consolidation Therapy

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Understanding AML Induction and Consolidation Therapy from Patient Empowerment Network on Vimeo.

Dr. Hetty Carraway, an AML specialist at Cleveland Clinic, provides an explanation of the role of induction and consolidation therapy in AML patients.

Dr. Hetty Carraway is Director of the Leukemia Program at Cleveland Clinic. Dr. Carraway cares for patients with acute leukemia and bone marrow failure states. Learn more about Dr. Carraway, here.

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Transcript:

Katherine:

Would you define induction therapy and consolidation therapy and tell us what the differences are?

Dr. Carraway:            

For most patients that are diagnosed with an acute myeloid leukemia, over the last 30 to 40 years we’ve used an intensive chemotherapy regimen that we call induction. Induction means that we’re trying to get the leukemia into remission with an intensive chemotherapy regimen. Classically, that has been two agents; one, a cytarabine based regimen along with an anthracycline, either idarubicin, danorubicin, or some anthracycline that’s similar.

Now, the cytarabine based therapy is a continuous infusion over seven days. The anthracycline is given over three days as an intravenous IV push, and so that’s why it’s kind of been nicknamed seven and three – seven days of cytarabine and three days of another anthracycline.

Now, that has constituted the induction intensive regimen in the hospital with the idea that that leukemia gets under control and goes away. More recently for patients, they can receive therapy that is not this inpatient, in-hospital, induction chemotherapy but rather use oral therapy combining with venetoclax, which is a Bcl-2 inhibitor, along with azacitidine, which is either IV or subcutaneous given to patients over seven days. The oral, venetoclax is every day.

That type of induction can also be given and is now an outpatient regimen and more often offered to patients that are older, over the age of 75.

That, too can be considered induction with the idea that once a patient is diagnosed with leukemia this regimen is started, and after one month or even two months on venetoclax plus azacitidine patients’ leukemia can get into what we call remission, where the blast percentages are less than 5 percent. Then, normal hematopoiesis of platelets being greater than 100,000 and a neutrophil count greater than 500 or 1,000, and the patient is then transfusion-independent.

In general, induction chemotherapy is that first round of chemotherapy that’s trying to get the leukemia under control.

Consolidation chemotherapy is when you use subsequent cycles of chemotherapy to keep the leukemia under control because we know that if we don’t continue to give some continuation of therapy that the small, little seeds of leukemia will re-emerge and leukemia will relapse.

Essential Testing in AML: How Results Impact Care & Treatment Choices

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Essential Testing in AML: How Results Impact Care & Treatment Choices from Patient Empowerment Network on Vimeo.

What tests should follow an AML diagnosis and why? Dr. Hetty Carraway, an AML specialist of Cleveland Clinic, reviews the essential testing for patients with AML and explains how those test results may inform treatment decisions.

Dr. Hetty Carraway is Director of the Leukemia Program at Cleveland Clinic. Dr. Carraway cares for patients with acute leukemia and bone marrow failure states. Learn more about Dr. Carraway, here.

Download Program Resource Guide

See More From INSIST! AML

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Insist! AML Resource Guide

Transcript:

Katherine:      

Hello, and welcome. I’m Katherine Banwell. Today, we’ll discuss how you can be proactive by insisting on better AML care and personalized treatment options. Joining me is Dr. Hetty Carraway.

Welcome, Dr. Carraway. Would you please introduce yourself?

Dr. Carraway:            

Hi. My name is Dr. Hetty Carraway. I’m one of the physicians at the Cleveland Clinic. I work as the Director of the Leukemia Program, and I spend most of my time caring for patients with acute leukemia and bone marrow failure states.

Katherine:                  

Thank you.  Let’s start with the basics. What essential testing should AML patients undergo following a diagnosis?

Dr. Carraway:            

This is a pretty standard workup for patients that have this diagnosis of acute leukemia.

For most of our patients we always evaluate with a peripheral blood count including a complete blood count with differential, typically a comprehensive metabolic panel, and looking at a test called a uric acid, which looks at the cell turnover and the cellular debris in terms of the burden on the kidney. We often will get a bone marrow biopsy with aspirate for patients, and in the diagnosis of leukemia typically that’s already been done.

There are tests that are sent off of that aspirate called a test for chromosomes, whether it’s comprehensive cytogenetics or FISH, for fluorescence in situ hybridization. We’re often testing using a study called NGS or next generation sequencing looking for specific mutations of genes known to be important in the pathogenesis of leukemia.

Furthermore, we often get a test called flow cytometry from that aspirate looking at the markers on top of the leukemia cells that help us to identify the blast population. So, I would say those by and large are the tests in the bone marrow biopsy that we get, which are innumerable and detailed.

They often take some time to get back, so at the time of the diagnosis patients know that they have a diagnosis of leukemia, but those additional chromosome tests or mutation testing that can take up to two weeks if not longer to get back. And so, it’s important to follow up on that information later on and say, has that testing come back? If so, how does that change any of what the decisions are moving forward?

Katherine:                  

Genetic testing can often be confused with molecular testing. What’s the difference between the two, and why should patients undergo the testing?

Dr. Carraway:            

The chromosome testing and the mutational testing help us to really classify the risk in terms of the leukemia itself, whether or not that leukemia is responsive to chemotherapy alone, or if it means that there’s a higher likelihood of that leukemia not being controlled with leukemia only.

In that setting, we often then move towards transplant for curative intent in addition to the chemotherapy. The reasons to get the information is to really help us better tailor the therapy for each individual patient. That information really does help us guide not only the upfront therapy for some patients but even the long-term therapy. It can be incredibly overwhelming to have too much information at the get-go, so in some senses it’s better to have these pieces as they unfold over time.

For other patients, they want to know what exactly the plan is going to be A to Z from day one. That is of course more challenging now that it just takes time to get this information. I think what they need to know is that we’re working hard to get that information.

As soon as we get it, we don’t hold back. We reveal and share that information and come together to say, this is what this data or information means, and these are some of the choices that we either recommend that you consider, and these are the risks and benefits to those considerations.

Katherine:                  

Let’s look at something that is similar to what you’ve just been talking about. How do test results impact treatment and overall care?

Dr. Carraway:            

They really can. When you asked me how come chromosome or genetic information is different than mutational information, the chromosomes can help us to figure out where patients land in terms of prognosis. That information is different than the mutational testing. Both of those pieces can help us figure that out.

The mutational test, I will tell you, does help us figure out are there targets on the leukemia that allow us to use therapy that’s directed to that mutation. The key example I’ll give is a mutation in a gene called FLT3. That particular mutation has an agent now that is F.D.A. approved called Midostaurin, and so once we know that a leukemia harbors a FLT3 mutation we often add a drug called Midostaurin to the backbone therapy that is used for patients.

Now, that’s important, and now there are more and more genes that when mutated we have novel therapies that direct against that specific tag that’s on the leukemia and helps to improve eradication of the disease or control of the disease if you will.

That’s different than the genetic information when we’re looking at chromosomal changes that may allow us to say in the rare instances of  favorable cytogenetics like a translocation of chromosome 15 and 17 consistent with APL, the treatment for that type of leukemia,  acute promyelocytic leukemia, is very different than what we do for the majority of other leukemias.  

The prognosis for that leukemia is also very different. It helps to tailor the regimens, and it helps to select specific therapy that may be helpful to each individual patient.

Katherine:                  

Dr. Carraway, you just mentioned FLT3. Would you tell us about the common mutations in AML and how these may impact treatment options?

Dr. Carraway:            

There’s a multitude of mutations that we’re now following in patients. The way that we follow them is by doing this next generation sequencing test at the upfront time at diagnosis.

The reason why we’re doing that is because those mutations can regress with therapy, or they can progress where you gain additional mutations that happen as the disease progresses. Even if it’s responding to therapy or as it loses response to therapy and reemerges, it may reemerge with different mutations. As a result of that, it may change what therapy we select. Our ability at this point in being to recommend exactly at what time points we are checking the next generation sequencing we’re still learning right now as to what are the key times to do that testing.

In general, most institutions are doing that next generation sequencing at the time of diagnosis, and then also for some patients before they go to bone marrow transplant and even after bone marrow transplant.

For some of those patients that unfortunately relapse, we’re also making sure to retest the next generation sequencing mutation testing to see are there new mutations that have come about that weren’t there before?

Katherine:                 

I understand there’s something called IDH. 

Dr. Carraway:            

You were also asking about what other mutations besides FLT3 happen in patients with AML. FLT3 is one such mutation. NPM1 is another mutation that often it frequents patients that have AML. Those two mutations happen in about 30 percent of patients with AML. There are other mutations such as DNMT3A, ASXL1, and TET2 that we typically see in patients with MDS or even a pre-leukemia state called CHIP. For other patients, we have mutations that are targetable like IDH1 or IDH2.

Those two mutations happen in probably 10 percent to 15 percent of patients diagnosed with AML. Why are those important? They’re important because we have oral medications that are pills that patients can take. In the relapse setting for many patients after induction or intensive chemotherapy, they can use these oral therapies to try and control their leukemia. These are pretty exciting. 

All of these oral therapies have been approved in the last two to three years in the space of leukemia, so it’s been a game-changer in terms of identifying these mutations and then identifying drugs that target those mutations. It’s really changed the landscape for patients with AML. It’s new information, and that’s why as patients you want to hear about this so you know what questions to ask and you know, can you tell me, am I a candidate for one of these oral medications that is now available for patients with AML?

Katherine:                  

Dr. Carraway, thanks so much for joining us today.

Dr. Carraway:            

Thank you for the opportunity to be here. 

Katherine:                  

And thank you to our audience. I’m Katherine Banwell.

Confusing CLL Terms Defined

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Confusing CLL Terms Defined from Patient Empowerment Network on Vimeo.

What is FISH testing? What is IGHV? Physician assistant Danielle Roberts explains the meaning of these often confusing terms and their role in disease monitoring and CLL treatment decisions.

Danielle Roberts is a physician assistant with the Bone Marrow Stem Cell Transplant (BMT) team at Winship Cancer Institute at Emory University. Learn more here.

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Transcript:

Danielle Roberts:    

So, a FISH test is a test from your either blood in your bloodstream or from your bone marrow biopsy. And it stands for florescence in situ hybridization. And this is a highly specific test that looks at the chromosomal changes with CLL. This can be done in the peripheral blood or in the bone marrow.

And it’s important to remember that when we consider genetic testing and CLL, we aren’t talking about inherited genes, but the abnormalities that occur within the CLL itself.

So, an IGHV test is a mutational test that stands for the immunoglobulin heavy-chain variable gene locus. This can also be done in the peripheral blood and the bone marrow biopsy. This test can help us determine treatment options as well as help with determining what high-risk features there are for your particular disease.

So, 17p deletion is the deletion of the long arm of chromosome 17. This can be seen at initial diagnosis or it can be acquired later on in disease progression. So, for all patients this is one of the more important tests that if you’re going to ask your doctor if you’ve had, you should ask at a diagnosis. If you’ve relapsed later on, you should ask again if that mutational status is being observed or checked in your follow-up testing.

17p deletion is something that can be acquired along the course of your disease progression. It is not always seen at initial diagnosis but can be acquired if you are relapsed or refractory. Therefore I recommend that every time you’re having peripheral blood for flow or if you’re having bone marrow biopsies, especially if it’s for treatment planning purposes, you should advocate to your physician team to make sure that this test is being performed as it will drive – or as it can drive treatment decision-making.

Practical Advice for Coping with a CLL Diagnosis: What’s Next?

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Practical Advice for Coping with a CLL Diagnosis: What’s Next? from Patient Empowerment Network on Vimeo.

After receiving a diagnosis of chronic lymphocytic leukemia (CLL), patients can have a variety of concerns. Physician assistant Danielle Roberts shares her top three pieces of practical advice for patients to move forward. 

Danielle Roberts is a physician assistant with the Bone Marrow Stem Cell Transplant (BMT) team at Winship Cancer Institute at Emory University. Learn more here.

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 Targeted CLL Therapy: What Are the Side Effects?

Transcript:

Danielle Roberts:       

My recommendations if I could have three things that I would recommend all patients with CLL do, 1.) It would be to have your financial information kind of in line or know how to find that. Unfortunately, a lot of the medications that we use to treat disease are incredibly expensive. However, there are really good patient assistance programs out there. In order to be able to apply for patient assistance programs you do have to submit your financial information to them. So, I would really suggest that you have access or be able to know where to find that.

I would also really recommend you talk to your family members in so that they understand what’s – where you are with your treatment and what’s going on. As a physician’s assistant, one of the questions I generally get is when they bring in a family member or somebody who has not been along in their journey for their treatment, if they’re asking lots of questions, that was and kind of diagnosis. So, I encourage people to talk about that at the beginning, so everybody understands where they are and what the plan for the future is going to be.

And then the last thing that I always recommend to everybody is to understand that not one treatment is right for everybody. Understand that things are going to change and we’re all going to grow and we’re going to learn with the process. But if you don’t tell your healthcare team what’s going on, we can’t help you. And we say that there is no such thing as a bad question to us. You’re never bothering us. That’s what we’re here for. Rather you tell us, even if it may be something you feel is minor, ahead of time so that we can address it and work towards a solution, if there needs to be one.

How Will I Know if My AML Treatment is Working?

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How Will I Know if My AML Treatment is Working? from Patient Empowerment Network on Vimeo.

During acute myeloid leukemia (AML) treatment, specific tests help to gauge a patient’s treatment response. Dr. Pinkal Desai details how diagnostic tests are used in monitoring the efficacy of an AML therapy

Dr. Pinkal Desai is Assistant Professor of Medicine at Weill Cornell Medical College and a hematologist specializing in acute myeloid leukemia (AML) at Weill Cornell Medicine. Learn more about Dr. Desai, here.

Download Program Resource Guide

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What Is the Patient’s Role in Making AML Treatment Decisions?

Transcript:

Katherine:                  

Once a patient has started treatment, how do you know if it’s working? How do you gauge that?

Dr. Desai:                   

When a patient begins treatment, whatever their regimen is, for the most part, it takes about a month to get into remission. So, initially, with any treatment we would use, the blood counts will actually go down. Everything is down, down, down. That’s important, and it’s good, actually, because if we can’t wipe out these cells, then we’re not going to. The patient’s not going to go into remission. It’s good that these blood counts drop and they keep like that for a month.

After a month, generally, is the first look on an average to see where it is, and that kind of depends on the regimen. For intensive chemotherapy, we take a look in the middle, like Day 14, to see did we wipe out all the leukemia? And can we modify treatment so that whatever might be left behind will clean out? For lower intensity treatments, it’s about a month. So, that’s the first sort of real look at whether a patient is in remission.

And again, when I say, remission is a morphologic criteria that we see the blast count are less than 5 percent, and the cells are – the normal cells are back to what is considered within normal limits or normal for that person’s age. And the idea, at that time, is to not only just confirm remission, but like I was saying, how good is the remission.

So, that’s where MRD testing comes into play. You want to see what you want to find, even if it’s by small numbers, what is the percentage of leukemia that’s left behind. 0.01 percent, 0.001 percent. This is important.

The goal is to ultimately get that down to zero, and that’s how we use it during induction, even when they’re going through consolidation, we’re episodically monitoring with bone marrow or blood testing for some of these molecular mutations that is there continued response from where we started off? And once the treatment is done, we are still, we’re seeing these patients on a regular basis, sometimes doing bone marrow biopsies at regular intervals, to again make sure that there is continued response. And can we see something different, or is there an emerging population of cells that are worrisome, and how do we modify our treatments to try to kill these cells?