Chronic Myeloid Leukemia: Latest Treatments

Leukemia Research Foundation

Thank you for joining us for the second of four sessions of the Leukemia Research Foundation's new and emerging treatments. The topic this evening is chronic myeloid leukemia. My name is Lindsey Whyte and I am the Director of Programs & Partnerships at the Leukemia Research Foundation. I would like to take a moment to thank our sponsors, our supporters of this conference, AbbVie, Astellas, Kite, Daiichi-Sankyo, Novartis, Merck and Pfizer. And we also want to thank our webinar partner Patient Empowerment Network.

 

The Leukemia Research Foundation's mission is to cure leukemia by funding innovative research and we also support patients and families. The Foundation has raised over $87 million in support of its mission since our founding in the 1940s, and we have funded research grants to over 600 new investigators worldwide.

 

Our support programs for leukemia patients and their loved ones include information and resources, education programs, peer support services, financial assistance, and a directory of other helpful organizations and resources. Just a few quick housekeeping items for the program this evening. All participants will be muted throughout the program due to the large number of participants. If you already submitted a question and registration, please know that we have your questions and we will do our best to cover as many as possible. You can also type a question into the q&a box at the bottom of the screen at any time during program. After today's program, you'll be sent a brief evaluation through email. Please do take a moment to complete the evaluation so we can improve our future programs and we'll have an idea of what topics might be of interest in the future. Also, this program will be recorded and sent to all participants after today, and it will also be available on our website. So be sure to visit that.

 

We are grateful today to have Dr. Gaby Hobbs from Massachusetts General Hospital with us. Tonight's present on CML. Dr. Hobbs is the Leukemia clinical Director at Mass General, and she's also assistant professor at Harvard Medical School. Her focus in her clinical and research activities is on myeloproliferative neoplasms and CML, and she previously served on the NCCN Clinical Guidelines Panel for CML. When she's not mentoring, teaching, conducting research, or seeing patients, you can find her training for her next marathon. Dr. Hobbs, I'm going to turn it over to you. Thank you so much for joining us.

Dr. Hobbs:

Thank you so much Lindsey, and thank you all for joining. I am very happy to be here today and we'll start out by just a little bit of an introduction about CML. Let me share my screen. Oh, I think you need to allow me to share Lindsey, sorry. Well, I'll talk a little bit about CML and the treatments that are currently available and then we'll end by talking about new developments. There have been two recent conferences that I'll talk about, one that just happened and one that's going to happen soon. And so kind of just make sure that everybody's up to date with the latest treatments. So without further ado, let me get started. Here's the outline that I mentioned. So let's start with a little bit of background just to make sure that we're all on the same page. So today the focus of the discussion is going to be on CML or chronic myeloid leukemia. CML is a very interesting leukemia because it is defined by one genetic abnormality. This is not a genetic abnormality that patients are born with. It's something that occurs inside of their blood forming stem cells. And it occurs when a piece of one chromosome attaches itself to a piece of another chromosome and it makes a new protein called the BCR ABL or the Philadelphia chromosome and patients with CML will always have a variant of this. There's no such thing as CML without a BCR ABL.

 

It accounts for about 15 to 20% of leukemias in the adult, not the most common, but the prevalence is increasing due to the fact that therapy is so successful. Unlike other leukemias. The median age or the average age when patients get diagnosed is in their fifties with a slight male predominance. Untreated CML can be devastating and it goes from phase, which is where most patients are diagnosed to a more aggressive phase called accelerated phase and ultimately to a disease that looks very similar to either acute myeloid leukemia or acute lymphoblastic leukemia. But thankfully this occurs very infrequently. So a little bit of history. In 1951, there was a doctor called William Damashek who described the concept of myeloproliferative diseases, including what he termed then chronic granulocytic leukemia, the discovery that these patients had a lot of white cells. And then in 1959 the Philadelphia chromosome was identified, basically what I mentioned at the beginning of this talk, where doctors were able to identify this novel change in a chromosome that said if you have this change, then patients have chronic myeloid leukemia. And here's kind of a picture of what that looks like in real life. So the cells are basically on the left side of the screen and that's just basically what a blood smear looks like. If you look at the blood of a patient that's newly diagnosed, there's lots of different cells that look very different ways, and at the bottom we see what's called a karyotype, which is basically a picture of all of the DNA inside of a cell. And what we see in CML is one piece of one chromosome, like I said, goes and attaches itself to another chromosome. And that was a pretty big deal when that happened. Now we have many ways of identifying this and actually much better tests for doing this. And so what's interesting with CML is that we find this abnormality, but then we can follow the levels of how many cells have these mutations to determine how well patients are responding to therapy.

 

So fast forward from the fifties now in 2024, we have four what are called TKIs or tyrosine kinase inhibitors that are available for the treatment of CML in first-line therapy. And that includes imatinib, the first one, dasatinib, nilotinib or bosutinib. And there are also other drugs that are available in later line therapy including a drug called ponatinib and asciminib.

(7:01):

Obviously we are very fortunate in CML and that there are many excellent available therapies, but there are still some challenges that remain, which include the fact that these medications are expensive, that some patients may not tolerate them because of chronic side effects and some patients may not respond well to them.

 

So how do these drugs work? So basically I told you about the fact that these two pieces of chromosomes attach themselves to each other. They make this new protein called the BCR ABL, and basically you can think of the BCR ABL as a broken thermostat inside of the cell. And so it basically keeps telling the cells, grow, grow, grow, grow, grow, and it stops listening to the signals of the body that say, we have enough, please stop. And so imagine this is a cartoon of the BCR ABL protein and basically the TKIs or the medicines that people take just kind of attach themselves to what's called the ATP binding site, which is the active part of the molecule. So let's say they turn off the switch and the thermostat or the switch in the light, and then there's a new drug called asciminib which binds in another part of that protein. But basically the end result is to say, please turn off you've had enough. And then what ends up happening with those cells is that they die and they go away. So what's interesting with this is what's called targeted therapy. It is specific for this genetic abnormality that happens inside of cells, which is really incredible. Prior to these medications, we would just give what's called old school chemotherapy, basically chemotherapy that kills any cell that's dividing. But here we're giving a specific treatment for a specific genetic mutation. So this is really the best example or one of the best examples of what's called targeted personalized therapy.

(8:47):

So now we have the problem which is of course a good problem to have of choosing the right treatment for the right patient. And so the different medications that we have available have different side effects. And here's just kind of a summary, so it's not that simple, but something to kind of think about. So patients that have pulmonary issues, problems with their lungs have fluid in the lungs for a variety of reasons really shouldn't be on dasatinib. Patients that have liver issues or intestinal issues probably shouldn't be on bosutinib because those are some of the side effects that has. People that are on lots of different medications have a lot of medical comorbidities, cardiovascular issues, are probably good candidates for Imatinib as that has less drug interactions with other drugs.

 

Patients that have high blood pressure should be monitored more closely if they're receiving asciminib or Scemblix. That's one of the new medications. And patients that have a lot of cardiovascular conditions like high blood pressure, have had strokes in the past or heart attacks in the past or issues generally with their cardiovascular system are probably not the best candidates to receive therapy with Nilotinib or ponatinib. So just to be aware, when you're talking to your doctor about therapies, there are different medications available and they can be chosen to ensure that the patient can tolerate them well based on the other medical problems that the patient may have.

 

Now this little chart here is taken directly from the NCCN guidelines. These are guidelines that are used by doctors nationally and internationally, and they're compiled usually by a group of experts that treat these diseases a lot.

(10:30):

And so it's very helpful for the treating doctor but also for the patients to know are they being treated the right way and are they responding to treatment the right way? And so basically in some ways treating a patient with CML requires being able to follow this chart, kind of like a recipe. So in the first three months of treatment, we want to see the level of that BCR ABL that I was talking to you about, the level of that protein go down from whatever it was a diagnosis. It doesn't matter what it was, a diagnosis to less than 10%. At six months, we want it to be around one to 10%, and then after one year we want it to be less than 1%. Sometimes patients with Imatinib or Gleevec may take a little bit longer. And then patients where we want them to be able to stop their medication, we really want that level to be much lower.

 

So people that are going to stop their medication need to have a level that's at least 0.01 or lower for at least two years, and they have to have been on a drug for a total of three years in order to be considered candidates. I'm happy to answer questions about that, but just to know that there are very well-defined guidelines that say, here's where a patient should be at different time points. And it's important to know where you are there to know if you're responding well to treatment.

 

So I mentioned this a little bit now that we have so many excellent drugs, we've realized after a variety of different studies were conducted that some patients are eligible for what's called a treatment free remission or a therapy free remission. And that means that patients that have been on their drug for three years that had prior evidence of having had a BCR ABL and then have a good molecular response. And the last two years that level was 0.01 or lower are eligible for discontinuation.

 

But it's important if you are going to be considered for discontinuation, that you recognize that you're going to have to be monitored much more frequently. So for the first month, you need to get blood work every month, and then after that it's every two months and then after the first year, it's every three months. About half of the patients will lose that response in the first six months, but the other half can remain off of their therapy for many years actually. So that's something that's definitely worth considering if you meet these criteria. And if you lose that response, then patients will go back on their drug once the level is greater than 0.1 and the vast majority of patients will get into a deep remission again once they start their drug and they should start the drug that they were on before unless there was a reason that that drug wasn't well tolerated. And so it's a good opportunity to try another drug, but it doesn't have to be.

 

And here's just a graph from the first study that was done called the STIM trial, and it basically shows that in the first six months about half of the patients will relapse, but then after that it kind of stays flat. So many patients, I have have many patients that have been off of their drug for actually many years and one of my patients this week asked me, so am I considered cured? I've been off of my imatinib now for four years. I was like, good question. So many patients probably are cured actually, but we are always hesitant as oncologists to use that word. So in addition to this study, many other studies have also been done and they have shown the same results. So because we know that it's safe to stop this with close monitoring is now included as part of standard of care. So if you meet these criteria, you can be considered for discontinuation.

 

Alright, so let's talk a little bit about updates in management and new treatments. So I could not give you a talk today without discussing Scemblix or asciminib. It's been all over the place and I'll explain why. There's also been some updates on ponatinib and then there's a variety of drugs that are in development. So even though we have excellent therapies, there are still some drugs that are being studied.

(14:31):

So asciminib is the newest kid on the block basically. So it was just approved recently in the third line. What does third line mean, it means that a patient has been treated with at least two prior drugs and asciminib was approved based on this study called ASCEMBL. All of the asciminib studies start with A SC, and it compared basically patients receiving asciminib to patients receiving bosutinib because BOSUTINIB is also approved in the third line or has an indication in the third line. And so they just wanted to see if you compare patients with asciminib versus with Bosutinib, who does better. And the primary endpoint of the study, meaning how they knew the study would be successful was the rate of MMR or a PCR level CML level of less than 0.1% at 24 weeks.

 

And what they found is very convincingly that in patients that had been treated with two prior drugs, asciminib much more frequently got people into these remissions called MMR or major molecular remission compared to bosutinib. And so this is what led to the approval of asciminib. And although the primary endpoint of the study or where they initially decided that the study was successful was at 24 weeks, the authors then published additional data with patients that had been followed even longer up to 96 weeks. And that's the graph that I'm showing you here and it continues to show that asciminib is better than Bosutinib in the third line setting.

(16:04):

So let's talk about some updates with asciminib. So ASC4FIRST, like I told you, all of the asciminib studies start with ASC, was a study that has been presented at a medical conference called ASCO, the American Society of Clinical Oncology and will also be presented, I think it's this coming weekend at the American Hematology Association meeting. These are two important meetings where they are showing the results of this study that basically is using asciminib in the first line, meaning patients that are newly diagnosed. And what they did with this study is they compared patients either on imatinib or on any of the other drugs that are available that included dasatinib, nilotinib and bosutinib to asciminib. And what they found is that asciminib is very well tolerated, it is able to get patients into deep remissions quickly and it's able to do that more frequently than the other drugs.

 

And so the question that we have now is what does that mean for us and our patients? Will we have a asciminib approved by the FDA to be utilized in first line? And if so, should everybody receive asciminib upfront or who are the patients that should receive asciminib? And this is not the first time that we're in this situation. To give you a bit of background, we first had Imatinib approved and after that came dasatinib and nilotinib and then after that came bosutinib. And so all of these drugs are excellent and now we have an even more excellent drug. But an important thing to note is that just because patients get into remissions faster doesn't mean that patients are living longer with any of these drugs. And so the reason why the guidelines have four drugs available in first line is because, although for example, dasatinib and nilotinib will get people into remission faster than imatinib, when patients are followed for many, many years, none of these drugs has demonstrated that one group of patients can live longer than another group of patients.

 

In fact, patients do so well with these drugs that the life expectancy, the life expectancy of patients with CML today is basically that of normal individuals if they're treated appropriately. And that's a really important message. So for all of you who are thinking that you're going to talk to your doctors tomorrow and say, you're going to switch me to this new drug, I would say not so quickly. If you're on a good medicine and you're tolerating it well and you're in a good remission, that's good enough and it doesn't mean that you need to try something new just because it's potentially more potent. And so those are some of the questions that we think about. We have a lot of drugs that are available, but like I was showing you in the initial slides, choosing the right therapy for the patient isn't just about treating the patient with the strongest medication. It's also about treating patients with medications that they are going to be able to afford and to be able to tolerate. A really important message that I didn't mention before, but I really feel strongly about is that for CML where patients are going to potentially be on treatment for many, many years, the treatment can't be worse than the disease. And so making sure that you're on a medication that you tolerate well, where you understand what the side effects are, how they're going to change over time, et cetera, and that you have good support from your clinical team to make sure you tolerate the medicine is really just as important as taking the medication. The goal here is not to just kind of learn to live with all of these side effects, but really learn to figure out how to mitigate those side effects or eliminate them altogether. But that being said, of course it is really exciting to have another drug that will potentially be available in first line, especially a drug like asciminib that really is truly very well tolerated.

So there are other studies that are being done with asciminib. One is called ASC4START, where they're comparing asciminib to Nilotinib. There's another study trying to see if patients don't get into a deep remission, what happens if we add another drug to asciminib? So remember that cartoon that I showed you at the beginning of the presentation, asciminib works in one area of the BCR ABL and the other drugs work in another area. So a lot of the asciminib studies have actually investigated using two drugs together to see if we can get deeper remission in some patients with two different drugs. And there may still be a place for that actually. There may be some patients that really do have very resistant disease or very difficult to treat disease. And for some of those patients in the future, the standard of care may include treating them with two different drugs to get them into remission. So that's something that we all have to stay tuned for.

 

ASC2ESCALATE is a study that's also going on right now using as asciminib either in first or second line. The important thing about this one is that there is a little bit of debate based on the guidelines, the American guidelines, the NCCN guidelines say some things and the European guidelines interpret this a little bit differently. But basically we sometimes don't know if we should try to get our patients into a very deep remission or not. And so we have sometimes patients that have a remission that's okay, it's less than 1%, but it's still detectable at above 0.1. And so when people live between 0.1 and one, we kind of feel like we'd like to have a deeper remission, but we're not really sure if that's beneficial and or if it's worth changing them to another agent.

 

And so the ASC2ESCALATE, “escalate” like the study says, is basically testing that to say, do you have patients that are in this kind of okay remission but not the deepest remission? Can we make that remission deeper by changing them over to asciminib? Really the main reason I think that to do that if we do that outside of a clinical trial would be to try to see if, by switching to another drug like asciminib, we're able to get patients into deeper remissions that then make patients eligible for discontinuation because patients that live with a PCR level between one and 0.1% are not going to be eligible for discontinuation because we know the moment they stop their drug, the levels are going to go up. And so all of these studies are interesting. And so of course we have lots to look forward to over the coming years when these studies are presented.

 

So now let's talk a little bit about ponatinib. So ponatinib is approved in third line for patients that have a mutation within that BCR ABL protein called T315I. That's a mutation that we all worry about because it makes the other drugs not work. And we know that ponatinib and asciminib work for this mutation, but all of the other drugs do not work against this mutation. ponatinib is also approved just generally in third line. The problem with ponatinib is that it is associated with significant cardiovascular complications. This can include blood clots or heart attacks and things like that.

 

So there was a study called OPTIC that tried to study different dose levels, so starting patients at one dose level and then deescalating meaning lowering the level of ponatinib that they were receiving. And the hypothesis or the question that this study was asking is if we do that, if we start at a high level and then once patients achieve remission, we decrease the dose, can we minimize the side effects of this medication? And the answer is yes, that the safe approach and it can minimize side effects. But they recently presented the four year follow-up of patients with the T315I mutation and an important finding from this four year follow-up demonstrates that even for this group of patients that we really worry about those with the T315I mutation, ponatinib continues to show efficacy for this group of patients. So that's really important. And other key takeaways are that the 45 milligram starting dose, which is the standard starting dose, is the most effective in particular for T315I patients and patients that do not have this mutation can definitely safely deescalate to 15 milligrams daily so that they can have continued efficacy, meaning continued response with less cardiovascular toxicity.

 

So in addition to all the excellent drugs that we have available, there are a variety of new studies with new agents or combinations that are going on. And I'll tell you about a few. So there is an ongoing study using a drug called ruxolitinib, which some of you may have heard about. This drug is called Jakafi and it's used to treat other conditions and they're combining it with CML drugs. And what they found for this study is that the response rates appear to be in combination when patients receive ruxolitinib plus CML directed therapy. And then the goal of this combination would be that more patients are then eligible for discontinuation. So this is not approved yet, it's just being studied, but the results so far have been positive.

 

In addition, we have the drugs that are already approved and that's in the first row, but then outside of the US there's a variety of other drugs that are now approved as well. So there's other agents that exist which may be relevant if some of you are not in the United States. And then there's other drugs that are in development. So even though we have a lot of excellent medications, there's drugs that are in development. So there's a medication called vodobatinib that is a third generation drug, although it does not have activity against T315I, another one called a fourth generation drug vamotinib that does have activity against T315I and other medications that were based on the structure of ponatinib. And then we have other agents, the TERN or the TGRX, which are similar to asciminib that are also being developed, basically trying to block that new region of the BCR ABL molecule, but doing it maybe in a more specific way or with less side effects. So lots of drugs that are being evaluated to hopefully give us more options for our patients. Thank you so much for your attention. I'm happy to take questions.

Leukemia Research Foundation (27:01):

Okay, thank you so much Dr. Hobbs. That was really great. I thought it was very helpful that you laid it out one step at a time and very understandable. We have a couple of questions that were submitted live.

Dr. Hobbs:

Okay, I'm happy to try to answer those.

Leukemia Research Foundation:

Yeah, I think generally speaking, I think one of the basic questions is what if the BCR ABL level is not detectable for some reason?

Dr. Hobbs:

That is a great question. I'm glad we started with that. So remember what I told you at the beginning of this talk, there's no such thing as CML without a BCR ABL, but it is true that some patients have a unique transcript of their BCR ABL and can't be identified by usual PCR. And so this requires probably a deeper conversation with your physician, but there are many ways of quantitating or to know where you're at, like you asked. So for patients that have different transcripts, so not the typical one that's measured with what the assay that we use all the time, they can do a test called FISH, just like the food fish and that can identify patients that have unusual transcripts. It's not as precise, but it can definitely be used to at least know if a patient is in the right track. When patients are monitored by FISH, they're unfortunately not going to be eligible for discontinuation in the same way that a patient would be if they had a usual transcript. We just can't measure it that deeply, but at least it gives us a good sense of where we're at. So there are ways, and if there's no BCR ABL that has been detected ever either through FISH or PCR or initially that picture of the chromosomes called karyotype, and I would really call into question the diagnosis of CML.

Leukemia Research Foundation:

Great. And then we had several questions that were submitted in advance of the program, so I'm going to go to that and in the meantime, I just want to invite anyone who has any questions to go ahead and put it in the q&a section there. So one of the questions, there's several questions here that are dealing generally with side effects of treatments and one specifically is talking about the difficulty of actually administering the treatment. So they require using gloves to take the treatment. Are you able to talk at all about difficulties that patients may have depending on what treatment they're on?

Dr. Hobbs:

I think that happens a lot where patients go to the pharmacy and bells and whistles ring and when patients are getting that medication and it's like, oh, this is toxic substance and don't touch it, et cetera. And I would say I probably wouldn't worry too much about that. Some of my patients put it on the cap of the bottle and just put it in their mouth. I guess the main point really is just don't be handling it for a long time, but I wouldn't really worry too much about it.

Leukemia Research Foundation:

Okay, great. And then what about other side effects? There were several that were mentioning the questions that were submitted prior to the event, so severe nerve and muscle damage, some concerns about effects on the liver.

Dr. Hobbs:

Okay, yeah, sure, I can come in generally. So these medications, like I showed you at the beginning of the presentation, are associated with a lot of side effects. The first thing is it's important for your clinicians to know the side effects that can occur from the medications that you're on. So for example, if you're on dasatinib and you have fluid around the lung, that's because of the dasatinib and so the medication needs to be stopped until it goes away. If you're on a medication like bosutinib, that can cause abnormalities in the liver function for example. And so similarly, the medication may need to be held until the side effects get better and then maybe the dose needs to be reduced. And so if you're a patient that's experiencing what you think is a side effect, it's important to be able to ask your clinical team, is this a side effect of my medication? Could this be a side effect of my medication? If it is a side effect from the medication, it doesn't mean that you continue to take the medication regardless. It's important to know that there are ways to make those side effects go away.

 

Now if your doctor or your nurse practitioner, whomever you see has tried to make those side effects go away by stopping the drug or lowering the dose and those side effects are still there, then one needs to ask, are my side effects really from the medication or is this maybe not the right medication for me? Now that specific question about nerve damage or muscle damage, really that would be an unusual side effect from one of the medications used to treat CML. And so that's a moment where I have to say, is there something else that could be causing it? And if the answer is really, you've seen neurologists and you've seen all sorts of doctors and really they cannot find an answer, and the only drug you're taking for example is the medicine to treat your CML.

 

Sometimes people have strange side effects that just aren't reported commonly because they're unusual. And I would say if you're in a good remission or even if you’re not, if this is a debilitating side effect and there's no way to know if this drug is contributing to that very severe symptom, then that medicine probably needs to be held and it needs to be stopped until that symptom goes away or not, and we could consider trying another medication. So I think the message that I would like to communicate is that whether or not your symptoms are mild or severe, you don't have to live with them. It's important to advocate for yourselves. Ask your doctors, do I have to live with this? Is there something that can be done? If I'm in a good remission, can I lower the dose of the medication? We know that that can generally be done safely actually, especially if you're going to be closely monitored, and that's really a great way of lowering the side effects of medications.

 

Many times when you read clinical trials, I read them both as an investigator and then as a physician that takes care of patients. It's funny, many of the side effects that are reported are on the severity of these side effects and they talk about serious side effects, but the ones that are often overlooked are the ones that are the chronic, not as serious ones that patients live with every day, but that truly impact quality of life significantly. So even if it's a minor side effect, it doesn't mean that it's a minor impact in your life. And so it's okay to ask questions and it's okay to know that it's possible to lower the dose of the medicine or just switch you to something else. Things can be done to make you feel better.

Leukemia Research Foundation:

Yeah, I liked what you said earlier. You said very clearly the treatment itself should not be worse than the disease, right?

Dr. Hobbs:

That's right. We're lucky in CML.

Leukemia Research Foundation:

Yeah. So I think general message that people can take home is if their doctor is not able to work with them on whatever they're taking and find some better options, something that works better for them personally, then what's the next step? Should they try and find a different doctor, would you say?

Dr. Hobbs:

No, I think you have to try, I think to try to ask the questions, come prepared to clinic. I think one thing that I realize happens often is that you rush to get to your appointment. The Dr. may be busy and in a rush, you forget all the questions that you had thought about in between the appointments. But if you come to that appointment with a list of questions, you can make much better use of that appointment. And if you see that despite asking, despite questions, despite wanting information, you're just not getting that information, not a bad idea to seek another opinion.

Leukemia Research Foundation:

Okay. We’ve got several more in the queue, so let's go to those. One person is asking about grapefruit, so I know that's an issue.

Dr. Hobbs:

That is dependent to each of the drugs, and I think that's an easy question to ask with pharmacy. Yeah, there are many medications, not just CML medications that can interact with many drugs and with grapefruit juice in particular. And so if you've been told that you're on a medication where you can't take grapefruit, unfortunately you can't take grapefruit.

Leukemia Research Foundation:

So his question was what is the concern or what should he look out for? Do you know or is that a question?

Dr. Hobbs:

Just needs to be avoided because it can interact with the way that the drug is metabolized. And so I'm sure if you have a little bit of grapefruit one day, it's fine, but it's just not something that you should have all the time.

Leukemia Research Foundation:

Okay. I was diagnosed with BCR ABL one minor P 190 value high positive. Can you speak to the P190?

Dr. Hobbs (36:26):

Sure. So there are many different sizes of proteins when BCR joins with ABL or that chromosome nine joins with that chromosome 22, the most common size, the P and the number refers to the size of the molecule. The most common one for CML is P 210. The most common one for acute lymphoblastic lymphoma is P 190. However, there are some patients that are diagnosed with P 190 CML, and the only thing that is important to know about that is that when you go to the doc, they need to monitor the P 190 levels. I've definitely had patients where I'm like, oh, hey, your CML level is undetectable. And then I realized, no, it's not undetectable. They just check the P 210. If they run the test for the P 210, it'll look like you're in a deep remission, but you're not. So they just need to follow the P 190, but it's possible that the P 190 is sometimes harder to treat, more resistant to therapy, but not always. And so it doesn't have a lot of treatment implications. It has more implications for monitoring

Leukemia Research Foundation:

That same person. I could not tolerate bosulitinib and have pleural effusion on Sprycel. Are we trying to figure out what she should be on?

Dr. Hobbs:

Got it.

Leukemia Research Foundation:

It's a specific situation.

Dr. Hobbs:

Yeah, I think that I'll say one general thing to that. For patients that are switching therapies, I would say that there are kind of two main categories. You're either resistant, meaning the drugs don't get you into remission even if you're taking them every single day or there's intolerance when a patient is resistant. That's a different situation where you can't go from drugs that are considered second generation like dasatinib and nilotinib and then go down to imatinib, which is considered first generation. You have to move up to third generation like asciminib or ponatinib. Now, if patients are intolerant, meaning you're having lots of side effects from the medications, then any of the drugs that are approved are available to you. And so then the question is which one should be the next one to try just based on the side effects you've had before?

Leukemia Research Foundation:

Okay, this is an interesting question. Did we hear it correctly that we are born with CML?

Dr. Hobbs:

No, definitely not. We are not born with CML. That mutation that occurs is not something that you're born with. It is not something that you pass on to your children. It is something that occurs in our lives in our blood forming stem cells. So that mutation that I've been talking about the whole night is something that is what's called acquired or you pick it up in life. So when your cells are dividing and making new cells, which happens all the time, one of the cells made a mistake in its DNA. So one of the cells didn't pass on all of its DNA to the next one in the right order. So basically if you're a builder and you have blueprints to make houses in your neighborhood, they all look the same. Builder was walking to the next house and they lost a page of the textbook. That's what happened. It's not something that occurred when you were born. It's something that occurred in life.

Leukemia Research Foundation:

Alright. Another sort of situation described by a patient, they were on Sprycel, had fluid buildup in their lungs, but went into remission within four months and the dosage was reduced. Does that mean they can go off medicine?

Dr. Hobbs:

Great question. So not an uncommon scenario. Sprycel or dasatinib causes fluid buildup in the lungs pretty frequently. Lowering the dose of the medication is the right thing to do after a patient has had fluid buildup in the lungs. If the patient continues to have fluid buildup in the lungs despite being on a lower dose, then that patient should be considered for another medication. Now, if the patient is on the lower dose and tolerating it fine and not having fluid builds up in the lungs, then no, the medication doesn't need to be, doesn't need be changed.

 

Now, separate idea entirely. If this patient has been on a drug since 2020, now it's been four years, and if for those years the remission has been deeper, meaning a smaller number than 0.01 for the last two years, then yes, you are eligible for what's called a treatment-free remission period or stopping your medication. But you have to meet that criteria. So it's important that you don't go ahead and stop your medication now, but that you talk to your doctor and say, do I meet criteria for discontinuation?

Leukemia Research Foundation:

Okay. I think we've got to most of the questions. Let's talk about this one. I have had cancer for more than five years, still not in remission yet. I asked my doctor, is there a clinical trial I can get into for better care? Didn't give me an answer. So did I wait too late to try clinical trials?

Dr. Hobbs:

Great question. And I would say that it's hard to answer not knowing more about your specific case. I would say the first thing is if you've been on a drug for five years and you're still not in a deep remission, is your remission. If the remission is okay, like that level of less than 1% and you're feeling well with the medication, sounds to me like you're doing fine. If you're not tolerating the medication fine and you're not in the deep remission and you're not a candidate for having the drug lowered, there's lots of other drugs that are available now that can be tried. And so I would say before even considering a clinical trial, I would say, have you tried the other medications and have you tried asciminib, which is the newest one? And then lastly, yeah, you can consider a clinical trial, but recognize that clinical trials for CML don't happen that frequently. And so I would say not everybody with CML needs to be on a clinical trial. So there's lots of questions to ask your clinical team. And going back to what Lindsey and I were saying before, if you're asking questions to your doctor and you're not sure if your remission is okay, if your remission is safe and you're not getting answers about are there other drugs available, then it sounds to me like you need to either ask those questions again or go elsewhere.

Leukemia Research Foundation:

I like the suggestion though, going prepared to the encounter with your doctor and your care team with the list of questions, and that way they understand that you really are looking to get some very clear answers because something needs to change. Okay. Is it common for a drug that has been working for several years to suddenly stop working and not rebound?

Dr. Hobbs:

It's pretty uncommon for patients that have been on a drug for many years to all of a sudden lose their remission. But certainly it can happen. It's important to ask the question of why is that happening? Is the patient having a hard time taking the medication or is the patient on a new medication in addition to the CML medicine that's maybe interacting with it and making that drug lose its efficacy? And if the answer is no, nothing else has changed, then it's important to really ask the question, is something changing with the disease and are you a candidate for another medication?

Leukemia Research Foundation:

Well, we just keep getting, oh, well, we got a nice compliment.

Dr. Hobbs:

Good, thank you.

Leukemia Research Foundation:

Thank you. Yeah, so I think we've gone through a lot of questions and I think we've gotten a lot of answers today, so I thank you very much for that. I'm going to remind everyone that we do have a survey so we can get some feedback. I'm going to put back up the slide with the sponsor information to say thank you to them for helping us put on this great program. I'm going to thank Dr. Hobbs for your great presentation and all the information you shared, and I think some really great hope for the future for CML patients. Lots of options already, and also some very great options on the horizon. So I think that was very helpful to hear and I think we'll say thank you and goodnight.

Dr. Hobbs:

My pleasure. Thank you so much for the great questions and for inviting me.

Leukemia Research Foundation:

Okay, goodnight everyone. Thanks.