Introduction: Chronic Myeloid Leukemia (CML) as a Model for Targeted Treatment

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the third of 11 meetings we’re doing here in this meeting, in the ONS Congress, and this morning we’re going to be talking about chronic myeloid leukemia, one of the most interesting corners of medical oncology.

We have a great faculty today: our nursing faculty, Ms Ilene Galinsky from the Dana-Farber Cancer Institute and Ms Sara Tinsley-Vance from the Moffitt Cancer Center in Tampa. We also have Dr Michael Mauro from the Memorial Sloan Kettering Cancer Center in New York and Dr Neil Shah from the University of California, San Francisco in San Francisco.

As in all of our programs, we will be discussing the use of unapproved agents and regimens, so please consult the package inserts for various agents for more information.

We’re going to be posting all 11 programs on our Oncology Nursing Update podcast. If you don’t have that, just go to your phone, hit podcasts, type in Oncology Nursing Update, and follow us. We already have a couple of programs posted there as well.

As I mentioned, we’re doing 11 programs here, and we’re talking about more than just a specific cancer. We’re talking about oncology nursing and oncology in general, and there are a number of themes that we’re trying to draw out. And in particular we’re really here to listen to our faculty. I always loved making rounds when I started my training as an intern, and we really carried over that idea of really being able to pick the brains of the experts in the field. We’re really thrilled to be able to have these 44 faculty members join us here today.

One of the things we talk a lot about is the triad around the patient, the physician, the medical oncologist usually, oncology nurse and the patient and their loved one and the dynamic between them. And in particular one of the themes in general in oncology, in all of our work, is the idea of personalizing the care to the specific patient.

You’ll hear a lot of discussion about personalizing based on tumor factors, such as stage of the disease, but in particular biomarkers in the cancer, a big theme in oncology. And also the patient themselves, biopsychosocial factors that are important to consider in managing these patients. And in particular we’re talking about new agents. There’s so many new agents, fortunately and very excitingly, coming into oncology. That’s in every single one of these programs and in every cancer right now, there’s an explosion of new agents.

And finally a theme we’ve had for many, many years, we’ve been coming here for 17 years now, is what we call “the bond that heals.” That the relationship that you have with your patients is highly valued, it goes beyond any treatment you give them, and I think you all in clinical practice know that.

So we’re going to start out this morning, and I just wanted to — this is where we’re heading. I just want to chat a little bit about the evolution of the treatment of CML, and then we’ll get into first- and second-generation kinase inhibitors, where we are in terms of recently. Then we’ll get into, again, new agents, asciminib, another tyrosine kinase inhibitor that’s very, very exciting. We’re going to talk about that. Then we’ll talk about the important concept — you know, these patients, as you’ll hear, and you probably know, are treated indefinitely, but then the question is can treatment be discontinued and how we do that. We’ll talk about that. And then finally patients with disease progression.

But I just want to start out. And Mike, this is a slide you have in your deck, so we pulled it up here just so you can talk a little bit about it. Yesterday we talked about breast cancer. I consider one of the earlier forms of targeted therapy removal of the ovaries. And then tamoxifen that came along in the 1980s, again in breast cancer, what I would call targeted therapy of trastuzumab, we talked yesterday about HER2 as a target. But I think really the true era of what we now view as targeted therapy of cancer in general started with CML.

And Mike, I thought we could just spend a minute or 2 before we get started and talk a little bit about the background of how this all evolved. Such an amazing story. Can you kind of capsulize a little bit about how this all got started?

DR MAURO: Well, as you can see — thank you, Neil, and thanks everybody. So as you can see, we have this long history of understanding what the description of CML was, and a little bit about how it — the illness it caused. But really the breakthrough was understanding that this was the first human cancer linked to a discrete genetic abnormality, and that really was the driver of the cancer.

So a solo mechanism and a driver points you to the potential for targeted therapy. And then on the shoulders of giants, I think we’ve all worked with Janet Rowley, a cytogeneticist showing the Philadelphia chromosome, other scientists describing the activity of the fusion and how it caused cancer, and then the advent of targeted therapy, which is really our topic today. And the ball just ran after that with the list of kinase inhibitors approved, and the rapidity with which we saw remissions, and as I like to quote, training physicians how you can write a 2½-paragraph paper in the literature and get it quoted about as many times as possible with the report in 1960 by Nowell and Hungerford.

DR LOVE: So Neil, I’m kind of curious what was it like when imatinib came along, and what did you see in your patients?

DR SHAH: Yeah. So I had the good fortune of being a fellow at UCLA, which is 1 of 3 sites that had conducted the first-in-human study of imatinib, so we were seeing some of the first cases of response, which was incredible. I had worked on CML at the molecular level for my PhD years before with Charles Sawyers in the lab. He was not my principal investigator, but he was the principal investigator of that trial.

And it was remarkable. It was largely tolerable. There were, unfortunately, some patients who had significant reactions to it, adverse reactions, not so many. But then also there were patients who developed resistance, which is something that we and others went to study on in greater detail.

DR LOVE: Mike, can you comment on the diagram there on the right that talks about BCR/ABL?

DR MAURO: Yeah.

DR LOVE: And explain what it is. This is an alteration within the tumor cell. It’s not in the normal cells. It’s not a germline type of change. But what exactly is the abnormality?

DR MAURO: Yeah. That may be a little bit of history for me as well. That’s one of the original slides that Brian Druker, my mentor, who really was one of the original … positions, like Charles Sawyers and others, studying CML and developing imatinib.

So CML is linked to the BCR/ABL fusion, which is probably a fairly common genetic event, but causes cancer in a small number, thank goodness, where you have activation of a kinase, constitutive activation by genetic fusion. And the idea was could you develop a small molecule inhibitor that would inactivate the kinase and not have much other downstream or distant effects in the cell. So that’s how it was approached.

It's a little bit too simplistic because it only shows the only potential targetable area as being the ATP-binding pocket, and I’ll share a little later about asciminib, which targets another region in the kinase, so that just describes how to target — or what druggable targets there are in a defect in a cancer cell. And in this case we had a sole genetic abnormality and a very targetable lesion.

DR LOVE: Sara, any comments on the nursing perspective as this was evolving? Now we have a new paradigm. In the past we had chemotherapy trying to kind of acutely destroy the tumor. Now we’re talking about suppressing it indefinitely. Can you talk about how the nursing care evolved as time went on?

DR TINSLEY-VANCE: Yes. This is my favorite kind of cancer because it’s like a success story. And I came into the scene as a nurse in around 1990, and so I worked in transplant. We transplanted these patients. And so once we had a STI-571, the imatinib was approved — well, the STI was the clinical trial, it really was wonderful to see patients that we were going to transplant go on this trial and have a beautiful response. So I’m still taking care of those patients that I took care of in transplant, so you have long-lasting, durable relationships with people who you would have transplanted, and they may or may not have made it now having a normal life pretty much.

DR LOVE: Ilene, any comments, again? This is really a new paradigm for cancer treatment in terms of trying to suppress but not get rid of the tumor. Again, how did you see this evolving, particularly in terms of the nursing role?

MS GALINSKY: Yeah. So I, like Sara, was lucky enough to be around as a nurse during this time and then becoming a nurse practitioner, and to see patients that had a diagnosis that basically had a 10-year survival for chronic-phase CML, it changed their lives to know that they did not have a death sentence. And the biggest thing that I can say is to change a patient’s philosophy, that you can take a medicine, you’ve got to work with your provider on side effects, but if you don’t take it, it’s not going to work. But if you take it, and you see the results, that your PCR goes down, and that you’re feeling better, that makes patients actually be like this is going to change my life.

And I kind of use the analogy of hypertension. When your primary care doctor says you have high blood pressure, and they put you on an antihypertensive, patients take that, for the most part. And so this is how I kind of acknowledge when I teach them, to say the same thing. It’s going to be a chronic issue that now — and now 20 years later I can say you may be able to come off this therapy. And we’re going to talk more about who can be — stop taking their tyrosine kinase inhibitor.

DR LOVE: I think another thing was when we started to see these results there was a hope that this could be implemented throughout oncology, many different types of cancer. We were talking yesterday in terms of targeted therapy of lung cancer, for example, patients with EGFR mutations in their tumors, but it never — none of these other targeted therapy, lung cancer, ended up being as successful as CML. Hopefully that might happen in the future.

Sara, another I think theme that we talk about a lot, we talked about it yesterday, is the potential benefit to patients who are participating in clinical research. A lot of times we think about patients — helping patients in the future by participating in new trials, but also this is an opportunity for patients to receive an agent that maybe they wouldn’t be able to get in practice. And again, if you think about right at the beginning, when these patients started to take a drug, they still had a bunch of numbers on it, Sara, and yet they had this incredible benefit.

We did a video not too long ago of a patient with myeloma who’d been on a bispecific for 2 years, doing great, in remission, et cetera. And the day I did the video interview was the day that that drug was approved, which kind of tells you the message, the patients sometimes get benefits before those in the general population.

Sara, any thoughts, you have a lot of research going on, all of you do at your academic centers, about seeing patients actually benefit by participating in trials?

DR TINSLEY-VANCE: Yes. We do a lot of clinical trials, and as a nurse practitioner I saw a lot of the drugs that were second line, like the AMN107, which was FDA approved for nilotinib. And we also had, I don’t remember the name of the — the letters and the number, but we also had the clinical trial that — dasatinib is now available. And then we had imatinib at Moffitt. So it’s really a beautiful experience, and it makes you a true believer, and patients should participate in clinical because this is how we have home runs like we do with CML.

Biology of CML; Role of First- and Second-Generation Tyrosine Kinase Inhibitors (TKIs) as Initial Treatment for Chronic-Phase (CP) CML

DR LOVE: So let’s get into now the science and clinical management of these patients. We’re going to start out with Neil talking about first- and second-generation tyrosine kinase inhibitors, these small molecules, as initial treatment for chronic-phase CML.

DR SHAH: First of all, I just want to say thank you all for coming out so early. I have a special place in my heart for nurses. My mother is a retired nurse, and also — especially cancer nurses, because I know they have special needs, and you guys are their biggest advocates. My wife is a cancer survivor, and she speaks more highly of her oncology nurses than she does of her oncology physicians. So thank you for all you do. It is greatly appreciated.

So okay. I want to talk here about first- and second-generation tyrosine kinase inhibitors, which have been approved, as well as asciminib, which technically is not considered a second-gen tyrosine kinase inhibitor for complex reasons, but it is also approved as initial therapy for chronic-phase CML.

But first, okay. Do I just click on — oh, sorry. This is the advancer. Okay.

So just real briefly. One important thing, I think, to talk about is phases of the disease. Now thankfully in the US most patients are diagnosed in what’s called the chronic or early phase, but we know that if it’s left untreated it can progress to the accelerated and blast phase due to additional accumulation of mutations in other genes typically. And the more advanced it gets the harder it gets to treat, so our best chance for good outcomes is in chronic phase CML. I’m going to restrict my comments largely to the management of chronic-phase CML.

One thing I just wanted to also highlight here in this slide is there are — recently there have been some proposed new definitions for criteria, disease-phase criteria. While I’m all for progress, the thing that gives me some pause is that we have a wealth of outcome data with tyrosine kinase inhibitors based on the definitions that you see here.

And if you just now institute a new definition and say somebody with accelerated phase doesn’t — has maybe 12% blasts, when previously they would be considered chronic phase, that upstages them, and that means you’re going to treat them with a different dose of a kinase inhibitor. And there’s really no data to suggest that they would be better served with that, because again, all of our data comes from prior — from the old, established MD Anderson definition. So I think many of us — there’s some debate about this, but I think many of us do prefer the modified MD Anderson criteria. And pathologists will not always report that, so that can be something to really pay close attention to, in my opinion.

So this just kind of highlights, as I said, what we typically will see in the absence of treatment. I think Ilene touched upon this, that this is a disease that had a life expectancy of 5 to 7 years prior to the advent of tyrosine kinase inhibitor, and people would die of this almost — if they didn’t have a bone marrow transplant, and the vast majority of patients were not suitable candidates for a bone marrow transplant.

The disease can impact people before the age of 18. It’s uncommon, but it can happen. But really, we have quite a few patients who are in their 20s and 30s, and it can also impact people much later in life. So there’s a very broad distribution of ages that are impacted.

As I mentioned, the accelerated phase and blast phase are much more serious conditions, even today with the effective tyrosine kinase inhibitors that we have.

So this shows you just a Kaplan-Meier curve of that data. We don’t need to really go — and again, this is in 1980. That chronic-phase curve, which had 6 or 7 years, now that curve would sit above — between 0.8 and 0.9, with many of the people dying due to causes unrelated to CML. So now when we counsel patients we tell them with treatment that there’s probably a less than 5% chance that you will die of CML. Without treatment you’re looking at 6 or 7 years, and that is usually enough to motivate them, but some patients still do struggle with adherence, and this is a very important role that I think nurses can play, is, as was previously mentioned, make sure patients are actually taking their disease.

So these agents can cause a lot of side effects. I’m not going to go through all of these; you have access to the slides. But in the middle, there are the common ones. So they all can cause myelosuppression. They all can cause fatigue, musculoskeletal discomfort, elevated LFTs. And there are unique ones that are — more unique —that are more common with some drugs versus the other, so it’s important to be aware of this. There is no perfect drug for this disease, and sometimes we just have to find the right one really by trial and error — most of the time.

Sometimes patients may have pre-existing comorbidities that can lead to choice of therapy. I’m not going to go over this. These are relatively uncommon but it’s something to be aware of.

There are other considerations, which include not only comorbidities but other things here. A couple that I do want to highlight are the effective dose range. So the second-generation drugs are more potent. You can minimize side effects by dialing down the dose quite frequently in responding patients and maintain response. And then cost, there’s generic imatinib, there’s now generic dasatinib that is available through Mark Cuban’s pharmacy, and so we have to start as a society, I think, start to grapple with this issue.

This is a slide that just has my front-line dosing strategy.

This lists several of the notable characteristics of these compounds — of these drugs. The more plus signs the better. And again, as you can see, there’s no perfect drug here, but you can just look through this and kind of see how they compare based upon these various features that are important to take into consideration.

So this case I want to go to, I picked the case of a nurse who was incidentally noted to have leukocytosis just this past January. And she had a CBC performed 2 years earlier that was unremarkable. She was referred to a hematologist and diagnosed with chronic-phase CML. She has hypertension, bilateral hip osteoarthritis and anxiety.

She was started on a dose of bosutinib, interestingly at a dose of 500 mg, which is not the approved dose for newly diagnosed patients, and perhaps not surprisingly she suffered a lot of diarrhea on that dose, as well as elevated liver function tests. The dose was held, and she came to me for second opinion. We prescribed dasatinib, which really has almost no incidence of liver test abnormalities. This is relatively recently. So she started, her LFTs normalized, and her counts are looking normal. It’s too early to know how well she’s responding at a molecular level.

So with that I’ll turn it back to Neil.

DR LOVE: So just kind of curious what it’s been like. I’m always curious when I see healthcare professionals as patients, nurses and physicians, particularly those in oncology. What was it like working with her as a nurse? Did she have more questions than other people? What was it like?

DR SHAH: Yeah. Obviously, I mean a lot of our patients are medically — more medically sophisticated now than they were 20 years ago. In some ways, sometimes that’s a good thing. Well, it is a good thing, but as we all know, there’s a lot of misinformation out there. So some of our patients, not generally healthcare providers, but some of our patients come with questions that really come out of left field. But yes, nurses obviously are very attuned. And nurses, we have to really work hard, of course. It’s a very demanding profession. You do what you can to maintain quality of life, especially, while not compromising efficacy.

But yeah. I mean, it’s — to me it’s always a pleasure to work with people who have a medical background.

DR LOVE: Ilene, any comments? I’m sure at Dana-Farber you see lots of patients who are in the healthcare profession, nurses, physicians. Any thoughts on how it’s different taking care of them than other people?

MS GALINSKY: Well, I look at is twofold. As the clinician taking care of another clinician I have to remind myself that yes, they’re a clinician, as well, but I want to look at them as ai would any other patient. So I think that’s one important thing that I do differently. And also know that they may be a dermatologist or et cetera. They don’t know CML, and I think in a nice way we have to treat them with the respect that they have some knowledge base, but also explain that they need to let us guide them through this and treat them, as we mentioned earlier, like any other — any other patient, and to discuss things openly and do explain the disease, the goal, side effects and long term.

DR LOVE: Okay. So we’ll get into more granularity about this, but let’s continue on in terms of particularly this issue of first-line therapy and the use of various tyrosine kinase inhibitors. So Sara.

DR TINSLEY-VANCE: Yes. So this is a patient that I’ve been following for many years. He looked at our last visit, and he said, “We’ve been together 20 years.” And I’m like maybe we don’t want to say it that way. It sounds like we’re married or something. But I started taking care of him before his son was born, so I know his whole family, I know them by name, I know their vacations, and that’s a really wonderful experience for both of us, I think.

So he was diagnosed, if you remember the timeline, with CML in chronic phase in 1995. So that was a pre-imatinib era. And back then we treated people with interferon, so that’s what he got, and he tolerated it poorly, and so that was discontinued.

They evaluated him for an allogeneic stem cell transplant, but he didn’t have a donor, and he didn’t want to go to transplant. He’s like no way, it’s too toxic. And he felt well, which a lot of our CML patients who are in chronic phase feel well, so it’s hard to wrap their head around I need to go through this very toxic therapy.

So he underwent an autologous stem cell transplant in 1998 at Johns Hopkins, but he did relapse in 1999, and that timing was perfect for the introduction of a clinical trial, STI-571, which we now know was imatinib. And some people say that stands for “stop transplants immediately.” We didn’t know that at the time, but that’s how we remember STI. But it was very wonderful for him.

So he enrolled in the trial. The dose was not the dose we use now. He was on 400 mg twice daily. And imatinib does have a fair number of side effects. He missed doses because he had nausea and vomiting, but he did have a hematologic and cytogenetic response, which is really a good response.

But then in 2004 his white blood cell count began to rise, and his hemoglobin and platelets decreased. You can see his results on the right there. White count of 24.29. His hemoglobin was 10.6. Platelets were 70,000. He doesn’t have circulating blasts, so that makes us feel a little better. The spleen was also enlarged. He still felt well.

So we found out that he had a kinase domain mutation. That’s one of the things we do. If a person isn’t having the desired response, or things are not looking well, we check for a mutation. And we know in retrospect that that was sensitive to the AMN107 trial, which we now know is nilotinib.

So this is when I first started seeing him, is when he started AMN107. His dose was 400 mg twice a day. And he thought he was sterile from when he had his autologous stem cell transplant, so he wasn’t using any protection with his wife, and his wife became pregnant 9 months into the study. So we all freaked out, but you saw the picture of his son. His son is perfectly fine. There was that concern for potential birth defects, so they did a lot of extra monitoring of her pregnancy.

He started having a lot of chest pain, and it was radiating down his right arm, so that led to a hospitalization and per Novartis we had to reduce his dose to 400 mg daily. But that chest pain continued intermittently, but weaved into the clinical trial were regular EKGs, they have pharmacokinetic testing with lots of blood draws and study visits, so I really saw him quite frequently, and I was also the person who did all of his bone marrow biopsies.

So we had a lot of discussions. So he really does feel like part of my family.

And so we had to keep track of his medications, his symptoms. You grade the toxicities, and 18 months into the study his FISH for BCR/ABL was negative, so he had a complete hematologic, cytogenetic and molecular response, which is a wonderful response. And he still remains on that treatment today.

I like to use pictures to explain this gene, BCR/ABL, and how it produces the Philadelphia chromosome, and then what we’re looking for. You see karyotyping by G-banding technique on the left, which we get the cytogenetic analysis from the bone marrow biopsies, which we don’t always do those as we’re — nowadays as we’re monitoring patients because we have PCR that’s much more sensitive than just doing karyotyping. We also do FISH for BCR/ABL.

So I talk to patients about these results. But now we’re using the PCR for BCR/ABL, and we have the international scale. And so that allows us to compare results across different labs and know that it’s pretty similar.

So I’ll stop there.

DR LOVE: Alright. Well, maybe we can talk — you had some additional slides that I wanted to kind of get into in terms of side-effect management. But first, Ilene, I want to just go back and just for — can you clarify? You mentioned transplant, autologous transplant. Can you talk a little bit about what an autologous transplant is and how that differs from the other types of transplants?

MS GALINSKY: So an autologous transplant is they take the marrow cells from the actual patient and give them back. So you may now say why would you give someone back their cells that have an abnormality of the CML, and that’s why we don’t do autotransplants anymore. And the patient did relapse because there was positive mutation in the marrow, so we just kind of after a while gave him his disease back because the chemo you give with a transplant is not enough to wipe it out. So we don’t do autotransplants anymore.

The allogeneic transplant is when you take it from a related or an unrelated donor. You could do an umbilical cord transplant. But as we’ve all said, we hardly do transplants for CML patients, thank goodness. For those that Dr Shah said, high risk, or people that have literally failed all the tyrosine kinase inhibitors, we do then offer an allotransplant. In our institute probably last year we did 5, and we do a lot of transplants. Most patients you’re able to hopefully treat with a TKI, or if you have to, if they do progress, add some chemo, steroids or there are clinical trials for advanced disease.

DR LOVE: So I want to talk a little bit about life on tyrosine kinase inhibitors for these patients, particularly some of the tolerability issues that come up. But I’m just curious, too, about this patient, the man you just presented. How old was he when he was diagnosed initially?

DR TINSLEY-VANCE: He’s 59 now, so —

DR LOVE: That was 30 years ago, so in his late 20s.

DR TINSLEY-VANCE: Yes.

DR LOVE: I guess, as was mentioned before, one of the things about CML is you see a lot of younger patients. Any comments, Sara, about managing a younger — a lot of patients in oncology are older, and here you see a lot of younger patients, and you have the issue of patients, maybe they’re working or in college in their 20s, now talking about indefinite therapy.

DR TINSLEY-VANCE: Yeah.

DR LOVE: What are some of the issues that come up in these patients?

DR TINSLEY-VANCE: That’s a very good point. He’s a sheriff, and he was able to continue working, but it was like pulling teeth sometimes to get him in for all those study-related visits. That was a lot of — it was a burden on him, but he knew that if he didn’t find a treatment that worked for him his life would be much shorter. And once he had a child he became — he came to his visits like he needed to.

DR LOVE: Neil?

DR SHAH: Yeah. I just wanted to add in terms of adherence, barriers to adherence, of course side effects is one, and that’s where of course we can all play an important role by asking about tolerability. But I think another thing that this case highlights is it’s been our experience that people who are in this age range between 20 and 30 in particular, and even sometimes up to 40, they particularly struggle with this diagnosis.

When you think about other diseases that hit this age group, where your choice is treatment and you live a normal lifespan, but you have to take it pretty much every day, most likely, or you’re going to live just a few years. The only other diseases that fit into that category are Type 1 diabetes and HIV. So it’s really a big burden on these people to have to face that reality, that unlike all their friends, if they’re in their 20s, they’ve go to now take a medication every day pretty much for the rest of their life in most cases.

DR LOVE: Mike, can you comment a little bit on selection of a TKI? We started out with imatinib, then we had the second-generation TKIs, we’re doing to talk about asciminib in a second, but just focusing on the initial drugs, imatinib and the second-generation agents, in your mind how they differ, particularly in terms of tolerability?

DR MAURO: Sure. So I’m a runner, so I always use the analogy of it’s like running a marathon for these people, or ultramarathon, or Forrest Gump I guess is running indefinitely. So we have to pick our agents for the whole package, for obviously rapid and deep remission, but also it has to be tolerable. We just discussed how it could be someone — a 30-year-old sheriff who has no time for adverse effects and bathroom stops while he’s chasing criminals, et cetera. We’re particularly keen about family planning. Men, very minimal concern, but clearly — and we’re going to talk about treatment-free remission and cessation of therapy, particularly in a childbearing woman. I have a strong passion to try to help people with that story.

So when we’re picking the drugs we’re looking for something, obviously, that’s going to treat the disease and be really manageable, but then we get into the goals of therapy. And I think treatment cessation, which is a big one, is how we’re making advances, maybe, with our newer drugs. We pay a little bit of a penalty with the second-generation drugs with adverse effects, each drug has its own issue, and then I think we have some nice new additions, which really have minimal burden of new adverse events that really might push the envelope on a cure for CML, which is really where we’d like to go.

DR LOVE: So another point. When we do education for physicians our primary target audience is the general medical oncologist in community-based practice. These are the same offices that are seeing CML, but they’re seeing myeloma, breast cancer, bladder cancer, et cetera, et cetera. Everybody’s trying to keep up to date with all of the new drugs, and a lot of times very uncommon diseases, like CML, are treated in specialized centers. But general medical oncology offices treat CML, for sure, and it’s a sophisticated treatment, but it’s done in the community, and so I think we need to keep that in mind.

And Ilene, another overriding factor that we alluded to, but I’m curious how it plays out, is financial issues, financial toxicity to the patients. What do you see there?

MS GALINSKY: So that is a big issue for all oral cancer drugs, but specifically with CML. We know right away which 1 or 2 tyrosine kinase inhibitors we’re going to use on our patient. If we see a patient newly diagnosed in the outpatient setting, we’re used to this, the white count doesn’t bother us, so it allows us time to write the prescription, to see what the copay is and to allow for financial assistance.

When a patient gets diagnosed in the community usually the primary care doctor, or whoever sees them, sees the white count of 300,000, says you’ve got to go to the emergency right away, you’re going to die, you have leukemia. And when they come through the ER, then they see me and my attending physician, and we know right away that pretty much they have CML based on their blood counts, but obviously we say we need to do a bone marrow and send off these tests.

When they’re in the hospital I don’t let them leave until they have their tyrosine kinase in hand. So I’ll start it in the hospital, and then I make sure right away that I’m working with our insurance to make sure they can afford it and make sure it’s in their hand just for that reason, that there are insurance companies that unfortunately, despite the data, still don’t want to cover it. And some of them will say they’ll cover it, but who can afford the $10,000 copay? And that’s a really big issue that we’re struggling with.

DR LOVE: So Neil, another issue here is following the patient and determining whether they’re responding to treatment. Can you talk a little bit about the types of assays that are done and what you’re looking for at various points in time after you start treatment to indicate that you’re on a successful path?

DR SHAH: Yeah. I’ll just follow up on something that Ilene just mentioned about cost. I hope everybody is aware that generic imatinib is available. Sometimes there are patients who have like excess copayments, and then I tell them you can get generic imatinib for $35 a month through select generic pharmacies. And so we hope eventually this will be the case for other drugs.

But in terms of how we monitor the disease, in most cases we do at diagnosis want to get a bone marrow biopsy. That allows us to look at the chromosomal analysis, to do a chromosomal analysis, to see if there are other chromosome changes in addition to the Philadelphia chromosome, that might suggest a more concerning and more aggressive disease behavior.

But after that, for the most part, we just follow the quantitative PCR. This is a very sensitive test. It can be done on the peripheral blood. It’s typically reported on what we call the international scale. It’s like an INR for a prothrombin time. And so ideally you should be able to compare one lab to another. And the goal that we ideally want to achieve is after 3 months a level of 10% or less on this scale. And when patients are newly diagnosed it's roughly around 100%. Some patients are a little bit more, some patients a little bit less. You may ask how can you have more than 100%. It’s because it’s not really a percentage.

But after 3 months 10%, after 12 months 1%. That puts people in the best prognostic category. Patients who are responding really well, as was mentioned by Sara, like who have no detectable disease, they have less than 0.003%, generally speaking, and they are the ones who can potentially try to discontinue treatment, and we’ll talk about that a little bit later.

DR LOVE: So Sara. Again, I recommend that you check out Sara’s slide set. They go in detail a lot of issues about side-effect management. But just a 10,000-foot look, Sara, can you talk a little bit about cytopenias, fatigue, and fluid retention?

DR TINSLEY-VANCE: I think the ones that concern the patient the most, which might not be what concerns us the most, is the fatigue. So there are studies showing ways to manage the fatigue. We had a study that we did at Moffitt with our psychiatrists, or psychologists, I think it was psychiatrists, for fatigue management, and it was as simple as looking at their day and trying to schedule their day’s most important activities around the times when they have less fatigue.

For the fluid management, decreased salt intake. We really see more fluid problems, I would say, with imatinib. But we can work with them, sometimes give diuretics, look at their medication list. So we just work with the patient and do what we can to help them there.

DR LOVE: Mike, any comments on how you select a tyrosine kinase inhibitor? Are there any comorbidities that a patient might have that maybe point you towards one versus another?

DR MAURO: We’ve learned that some of the side effects of the drugs seem to include either accelerating or unmasking or even triggering vascular complications. But it’s really hard, because this is a population of patients, a little on average, maybe, in the US, that are 50, 60, although there are plenty of folks that are younger, unfortunately.

So that’s probably the one thing to mention. And it’s not that we have to do a very rigorous special agenda. We just need to be engaged with general medical care and probably cardiology, in many instances, and in select instances maybe cardio-oncology, the specialty of cardiologists that take care of cancer patients that know the drug side effects. And it’s as simple as just making sure we know if they have disease, so if it gets worse we can decide whether that’s a drug side effect or worsening from a drug side effect.

If they have hidden cardiovascular disease we should treat it, but that’s really just what these patients need anyway, and that — sometimes a cancer diagnosis brings people into the office for other care, and they kind of get on a little bit more of an agenda.

So when we’re picking the medication, that really isn’t a hard stop, but it’s certainly a consideration, and it’s related to line of therapy. In the front line, which we’re going to get to that in a moment, we have 5 choices, actually, which is complicated, but there’s some merit to thinking about some of the newer ones. When you get to later lines of treatment you may be thinking about a mutation or what they’ve had before or their health issues, and now you’re a little bit more tethered to certain decisions you have to take. But avoiding cardiovascular morbidities is obviously one of the most important things because it’s dangerous.

DR LOVE: Alright, Ilene. You wanted to comment. We wanted you to comment on some of the practical issues that come up in the management of these patients.

MS GALINSKY: Okay. So just in general, I think it’s important to know, as we mentioned earlier, that there’s 3 phases of CML. We’re going to focus today on the chronic phase. So there is different dosing schedules, et cetera, and different thought processes dealing with the patient in blast crisis or accelerated phase, but I’m going to focus on the chronic phase.

So imatinib, as we all know, is the first TKI. In my institute for newly diagnosed patients we usually start with imatinib or dasatinib, and I’ll explain why later. So imatinib is 400 mg once a day. You can take it with or without food. The major side effect is — from a clinician’s standpoint, is worrisome for us, is that it can, before it works, cause myelosuppression and thrombocytopenia. So it is important to monitor lab work initially. There’s appropriate dose mods if they get too neutropenic or too thrombocytopenic, and you can also consider possibly adding erythropoietin growth factors or thrombopoietic growth factors as well.

But patients, in my experience over the years, what bothers them most about imatinib is the periorbital edema and fluid retention. And it’s not a matter of shortness of breath. It’s more of the cosmetic and how they feel and look. So as a clinician you’re like okay, the drug is working, it’s okay, bu we can’t lose sight that this is a person that is living through this disease, and you want them to take the medicine, so you need to work with them on that. And sometimes it’s gotten to a point where despite dose reductions, I mean, I’ve had to switch people because they’re like I can’t take this anymore. So it’s always important to look at the patient as an individual, and you have to tweak things to meet them halfway so they do take their medicine.

Dasatinib is 100 mg once a day. Major concern, as we’ve talked about, is pleural effusions. People can have muscle aches and rash, as well as GI symptoms. This too can be taken with or without food. It does cause myelosuppression, as well, so just always be mindful of that and educate your patients if they do become short of breath or they notice weight gain. And on our exams, we’re really focused on O₂ sats and making sure that their lungs are clear. If you do notice, you would get a chest x-ray. Depending on the extent of the pleural effusion you would either hold drug, add a diuretic, or manipulate the dose. It all depends on the extent of the pleural effusion.

Nilotinib, black box warning, QTc syndrome history, cardiovascular complications. You wouldn’t want to use this if you know someone has hypertension or cardiovascular disease, as Dr Shah mentioned. You’ve got to be mindful of patients’ comorbidities, et cetera. This is BID dosing and to take on an empty stomach.

It is difficult to — especially twice a day drugs, to fast before, and then you can’t eat until 2 hours after, to adjust somebody’s lifestyle to that is complicated, and especially because they’re going to be on it for a period of time. So also when we’re thinking about what tyrosine kinase inhibitor you’ve got to think of where the patient is in their life and is it even feasible for them to try and do this. So I think that’s an important consideration.

We had a patient, and it’s public knowledge, he was a professional NFL — I’m sorry, hockey player, and he came to us, and he was started on nilotinib. And I don’t know how he did it, but through practice and several seasons he managed on the road every game to maintain the nilotinib fasting profile. So it can be done when you’re motivated, but in reality I think it’s important as clinicians to really look at your patient, and just because you think medicine X is their best choice, is it really the best choice for that person in front of you?

Bosutinib starting dose is 400, or if you have moderate renal dysfunction you would start at 300. It’s once a day with food. The biggest side effects my patients have with this is diarrhea, nausea, abdominal pain. I do not have a patient that is on 400 mg of bosutinib. Most of them are down to 200 or 100. It’s tolerable, and they’re responding, so that’s why we are okay with dose reducing them.

When you do dose reduce someone you can’t lose sight, too, of monitoring their molecular status and make sure they’re meeting their milestones. If they’re not, you need to look at why aren’t they. So we draw mutational analysis to see if they’re developing drug resistance or are they not responding because they’re actually not taking it because they feel so miserable on it.

Role of Asciminib for Newly Diagnosed CP-CML

DR LOVE: So I want to move on now and get into the newest player on the block, asciminib. As we’ve been talking about, what we’ll be talking about all week, the idea that often in oncology we start out with 1 drug, and within the class within a few — a short period of time now you see several different agents. You’ve already heard about a number of tyrosine kinase inhibitors, but clinical research continues. These drugs are not perfect. We’re looking for something better, and for sure it looks like we have something here in CML, very exciting. So Mike, let’s talk a little bit about asciminib.

DR MAURO: Sure. So maybe we’re mid-program. I just wanted to thank you guys again for taking interest in this disease area. What a great partnership we have all working to treat these patients. And a shoutout to everyone working at the top of your field and becoming an expert in, or at least knowledgeable, in a rare disease. And a shoutout to Joel Stettler and Jen Abillar-Wright, who may be in the audience, who are my teammates taking care of CML in New York. So thanks for coming.

You saw this slide, so we’ll go past this, and this is a great historical overview.

But I want to talk to you about asciminib. So if you remember that cartoon, which was in the last slide, it looked like there was only 1 way to block BCR/ABL, which would be by blocking ATP. We call that the active site. And on this cartoon, which is kind of complicated, on the left, that’s the yellow dot, or the yellow blob there, that’s where imatinib, nilotinib, dasatinib, bosutinib, ponatinib, all of the drugs we have so far, would bind.

In light blue is this other area of the kinase called the myristoyl pocket. So from the very beginning we knew that this could be a way to block this kinase, and the same people that made imatinib and nilotinib, the company Novartis, they, in the lab, the scientists in the lab, it was a long time coming, but we finally developed an oral available, well-tolerated myristoyl pocket inhibitor, or what’s called a stamp. It’s specifically targeting another area of the kinase.

You notice it’s in a different spot. So one of the ideas was maybe it would be different, and maybe we could combine medications. Those were the 2 principles why it was developed.

But is really has proven to be quite an excellent drug. I’m fast-forwarding all the way to this front-line trial. So asciminib was developed starting in 2012/2013. It was a very long trial, which showed that it was safe and tolerable. And in the beginning, of course, we were using it in people who have failed most treatments, and we thought maybe it would be an alternative to some of the higher-risk drugs we’re using later on.

It then was compared to bosutinib and was shown to be probably both safer and also better. Easier to take. We just heard Ilene mention the GI side effects from bosutinib.

So then the next step was a front-line trial. So this is it. So how do you design a front-line trial in CML? This was a good strategy.

So patients would come to clinic, and you’d decide what medicine you wanted to treat them with, and that was the assigned treatment. So it was patient/physician choice, which is the way it should be. And then if they were eligible they would be randomized to a trial where you either got a new drug or whatever you had decided would be the best. And that’s a great way to do it because you don’t pick which horse you want to run against at the track, you say I’ll run against everybody, and then we can see. So the patients fell into either an imatinib stratum, where the doctor had said imatinib — or the team had said imatinib would be the best choice, or one of the second-line drugs. And that’s the way the trial was built. They were looking to see if people got into a remission faster than previously.

And this data here, we don’t have to go over the details, but suffice it to say that asciminib was better than imatinib, most noticeably, which is in the middle, but also better than all of the choices combined. So it really did move the needle. It got people into remission faster. Now that’s important. It may not be everything, but it clearly can move people faster into safer remissions and maybe further along into the ability to think about stopping treatment.

Flipside would be what about side effects. And I think this is pretty clear as well. Asciminib, which is in green, was better than the blues, which are either imatinib or second-generation TKIs, related to side effects. Side effects that made people stop their medication or significant side effects that would have them slow down their dose or need to lower their dose.

This is a little bit too complicated, so I have a chance to review it. But would you look at the details? It actually was a little less likely to cause myelosuppression, a little less likely to cause liver and other issues, which are the most common things with imatinib. And with the second-generation drugs, same thing. It wasn’t necessarily harder on the patients when it came to blood counts. It was similar or even a little better and really limited some of the other problems we see. So it didn’t bring a new problem to the table, and it really backed off some of the ones we had before.

We’ve been very focused on what about the cardiovascular or we call them arterial occlusive events. And probably one thing to note is if you look at the middle of this slide, so again there’s a lot of data, but imatinib tends to really not accelerate or aggravate cardiovascular disease. But when it comes to our newer drugs, at least with asciminib, we’re not seeing much of an additional burden here. Other drugs, if you look at them specifically, might have a greater incidence. So I think that was an important readout. Of course you want to look at it a little further, but it was enough for the drug to get pretty rapidly FDA approved and put into the guidelines.

So this is the NCCN Guidelines, and I always mention that this isn’t — I know, Neil and others, we worked so hard on this, but it’s hard to pick a winner. In fact, it is noted that they’re listed in alphabetical order just specifically because we don’t want to say one drug is better than the other when it comes to the second-generation drugs.

So all the drugs are a choice, and it’s really an active discussion, and this data, I think, is really encouraging that we can get patients into remission deeper, faster perhaps, but there are some questions we still have about side effects, and we want to increase the cure fraction.

But maybe I can finish with a case, which I think might highlight the goals of therapy. This was a gal who came to me. She was 39 years old at the time, which is, I think, we’ve been focusing on kind of younger patients. Very busy woman, interior designer, half her time in London, half her time in New York. And she had some nonspecific symptoms but basically finally got into her GP for blood work and had very subtle changes. White count was 12, 13. Platelets were a bit increased. Finally, with a little bit more time it declared itself, and the white count was climbing, and her circulating white blood cells really were consistent with CML, as you can see on the bottom.

So despite the travel requirement, with a pretty active discussion, I was able to have her on to not the trial I mentioned, but a trial where we just were using asciminib for people in the front line. It’s through a nice group we have in North America called the CML — Khoury CML Consortium, or the Khoury Cure CML Consortium. She did very well. She had no adverse effects.

And this is her PCR. So I mentioned that the PCR, by 3 months you want it to get down to 10%. If you look at the yellow highlighted region, her PCR at 3 months was 0.01, so she basically was about a thousand times lower than she needed to be at 3 months. And then by 6 months she was into what we call a deep molecular remission. She didn’t really need to go any further than that to be fully successful on treatment. She has. She’s become either undetectable or below the limit of detection.

So this is the kind of woman who really — life was interrupted. She’s 39. She’s working, spending her time between New York and London, and now she has CML. So getting her into this rapid remission with confidence, that may be targeting the possibility for treatment cessation, which we’re going to talk about shortly, really was a beautiful thing.

And I’ll stop there and move the discussion on.

DR LOVE: So Neil, I’m kind of curious. When you think about asciminib, not so much from the clinical research perspective, but your clinical experience with the agent, how is it different than some of the prior TKIs?

DR SHAH: So I will echo that it seems largely very well tolerated. There are some exceptions to that. There’s some people who have musculoskeletal issues or — there’s no perfect drug, as I mentioned before.

So it was approved in the third line and beyond back in October 2021, and I had quite a few patients who had struggled with side effects on multiple tyrosine kinase inhibitors, despite dose reductions, and for a few of these patients switching them to asciminib has almost been a godsend. They’ve felt like they’ve gotten their lives back, and that’s been, of course, wonderful to see.

In terms of newly diagnosed patients, it was approved just this past October or November. So as Michael mentioned, it is another compelling option. As I alluded to in my initial talk, I think one of the things that we should maybe start thinking about a little bit as a society is how sustainable are the costs of some of these medications, especially when we have extremely cheap alternatives now. So that’s something, where all the brand-name drugs cost over $250,000 a year, but generic imatinib, for instance, through particular pharmacies, is $400 a year. So it’s something I think we’re going to need to grapple with, not only in this disease, this disease has been a trendsetter for so many aspects, but also in other aspects of oncology.

DR LOVE: Of course, though, patients with cancers often are so focused on the cancer, if they know there’s a drug that has some advantages they are often very interested in trying to take the optimal drug.

Let’s talk a little bit, Ilene, and you can go through some of the things you think about when you have a patient who’s going to receive asciminib. And what are some of the things you talk to the patient about?

MS GALINSKY: Thank you. I, too, just want to take a minute and thank you all for coming and listening to this and thank you for all that you do.

So I have not in my practice, and my clinicians, we don’t usually start with asciminib even though it got approved as first line. We usually start with imatinib or dasatinib.

Before I go into the whys and the side effects, I just wanted to mention, too, about the bone marrow sequence of what is recommended for the care of these patients. So I think it’s really important to know you should get a bone marrow at diagnosis for chromosome analysis and molecular. And then you can follow these patients by peripheral blood, FISH, or BCR/ABL.

You have to be mindful, though. There are some people that their Philadelphia chromosome BCR/ABL may not show up in the conventional way. So I have some patients that FISH doesn’t work. I can only do BCR/ABL monitoring, and I also have found we — it was mentioned, I think, on Dr Mauro’s slide, there is a small population that have a P230, which isn’t picked up on the normal PCR monitoring. That has to go to a separate place. So I think be mindful of educating your patients. Yes, you can mostly follow these patients after their first bone marrow with peripheral blood, which is great, assuming they meet the milestones and there’s nothing of concern that they are accelerating.

So I’m going to focus on asciminib as a switch too, and it’s usually because they have not tolerated their prior therapy. And a patient that I’m thinking of had a lot of pleural effusions, so before we switched we made sure there was no mutations to make sure that if there was we were putting them on the right tyrosine kinase inhibitor. So asciminib is more potent and seems to be more specific, and as we’ve all talked about basically has less side effects, so it’s better tolerated. And therefore, again, patients then are more apt to take it. There are mild muscle aches, GI symptoms, you can sometimes see an increase in blood pressure, but all those things are usually manageable.

So I wanted to talk. I followed this patient for a very long time. She got diagnosed around ’24, locally, and they had put her on imatinib and dasatinib. In looking back, I don’t know if I would have managed it the same way that they did. She had side effects. She had myelosuppression. They did various dose reductions. They did use growth factors. And she had a longstanding history of depression.

We switched her. We put her on the clinical trial for asciminib years ago, and she had manageable side effects. Initially, first she had some mild GI symptoms, but little, that you could control. She did have thrombocytopenia, but we thought that was due to her CML not being controlled by the time she came to see us. So she did require initial dose reduction and some growth factor support, but she responded nicely.

As a young woman, obviously, when she started these TKI therapies we talked to her about that she cannot get pregnant, and she was not in a relationship at that time, so it was okay. However, she did meet someone, and she did get married, so of course she wanted to try to have a family.

And so we had to make a decision what do we do? Her CML was beginning to get controlled. We obviously couldn’t in good conscience let her stay on this therapy. We were concerned, as we mentioned earlier. Interferon is really the only therapy that has been shown to be safe for females that are pregnant and on therapy to control their disease. But with her depression we were concerned. As you all know, if you’ve ever given interferon one of the main side effects is it can cause suicidal ideation and worsening depression.

So we had a big meeting with her psychiatrist and her and her husband, and she was willing to try that. She also, being that we had a small timeframe, she was getting hormone therapy to try to accelerate her ability to get pregnant. However, twofold, the hormones made her more depressed, the interferon made her more depressed, and several rounds of inability of success of this therapy made her almost suicidal, so we therefore stopped the interferon.

And then she was on a trial, so we wanted her to go back on her same dose, which was much higher than what it is approved for. And she couldn’t go back on the trial, but Novartis was able to do single-patient compassionate use for her, and she was able to go back on. And she continues on 160 mg, as you can see much higher, twice a day. Her PCR is the lowest that it has been of 0.014%, and last year they adopted a baby boy. And in her own words “this drug has saved my life and kept me from needing a transplant.”

DR LOVE: So Ilene, one of the things we’ve talked about over the years here in ONS is the idea of how often do you hear people say isn’t oncology depressing? And a lot of people bring up CML when they — we talk about that.

What’s it been like to take care of this woman?

MS GALINSKY: Taking care of her and other patients with CML with the tyrosine kinase inhibitors, it has been an incredible experience and honor. And to see these patients come in and bring in their families and that they’re thriving in their lives, it just makes my day. And I tell them every time, I can get through today seeing what we have done, and their struggle and our struggle of all the scientists to make this happen, it’s just been an absolutely — an incredible run. And to see, as we mentioned earlier, older patients are succumbing to natural things due to age not their disease, and I think that’s an incredible experience.

DR LOVE: Mike?

DR MAURO: Just as we’re getting into more of some of the discussion points, I mean, I think first I wanted to say I’m spoiled because I’m at MSK, and when I say I’m encouraging people for front-line asciminib it’s because I have a trial, so their cost is the best ever, it’s zero, because we hand them the drug. However, I think the trial data was — that’s a hard discussion that we have to have about cost of the healthcare system versus our patients, because when you have a drug that seems clinically better and clinically less adverse effects, if you’re a patient, that’s what you’d want to be hearing about.

But what we really need to hear, probably, is that this kind of new therapy will change the equation, and I think we don’t know that question yet. In the trial we’re doing in our academic centers in North America will we cure more people with this? So shorter treatment, maybe avoid some of the troubles that this gal had, or get my patient to her next stage of life, which she wants to have — start a family and get married, and she’s in her 40s. Her clock’s running down. So we’ve got a lot of discussions regarding newer drugs. And the bar has gotten higher and higher, and I think that’s very appropriate, but we should keep the discussion going, because it’s really important.

DR LOVE: Yeah. When you think about financial issues the best financial outcome is not to have to take therapy, and that’s what we’re about to talk about, curing patients so you can take them off the treatment. And it looks like asciminib hopefully is going to lead to that more often, more chance of cure, which of course is better for the patient and better for society.

Let’s continue, though, in terms of some of the practical nursing considerations, not just asciminib, but life in general on tyrosine kinase inhibitors, Sara.

DR TINSLEY-VANCE: Okay. Thank you.

So in October of 2024 FDA granted accelerated approval to asciminib, like Dr Mauro was talking about, for adult patients with newly diagnosed CML in chronic phase. And in October of 2021 there’s a specific mutation, the T315i. That should have been a little I, sorry about that. It had accelerated approval for treating those patients who had Ph-positive CML in chronic phase who had that specific mutation that’s difficult to treat.

So I’m going to talk about a lady that I’m seeing in clinic now who was in the community, and she had a lot of psychosocial problems, and also she got discontinued off of therapy without all of the guidelines that we have in place. So we’ll walk through her story.

This has been her rocky journey, and this is CML chronic phase. So she was diagnosed when she was 56, and she was started on imatinib, and she went into remission. We don’t have details about the remission. This is according to her story, so we don’t know was that just blood counts. And we know that that’s just the surface, that there’s a lot of disease under the surface that we can measure, and we want deep responses before we take patients off of therapy.

So her local oncologist discontinued the medication, and we don’t have details around that, but in 2013 she had a relapse, and she presented to the emergency room. At that time she started on nilotinib. She lost insurance coverage, and she was lost to follow-up until 2022, when she presented again, and she was hospitalized. When she explains it to me, she’s like I was almost dead. I had all of these problems. I needed 8 units of blood, and I also required platelet transfusions, which tells you really that her CML was very out of control. She also developed a clot, a deep venous thrombosis.

CML is the good myeloproliferative neoplasm, but like the other myeloproliferatives, when it’s out of control, and you’re not on medication, they get the other complications with — like patients with polycythemia vera get, because it’s a lot of inflammation going on.

So she was started on bosutinib, and she remained on that treatment for 1 year, and then she was lost to follow-up again. And then she presented to our clinic. We did a bone marrow biopsy showing the CML. You see the karyotype that we were talking about before, so 46,XX, and you can see t(9;22), that’s how it looks in the reports. That’s telling you there’s a translocation between 9 and 22. And then the q34.1 and q11.2 tells you where the translocation occurs. And then the 20 is telling you it was in all 20 metaphases. For sure it was CML.

There aren’t additional chromosomal abnormalities, which is good, but when we did mutation analysis she did have this T315i. So when you have that specific mutation your options are limited to ponatinib and asciminib.

The problem with ponatinib, as many of you may know, is she had a clot history, so that really wasn’t the best option for her. So she tolerated it poorly. She went into the hospital again, and she started needing a lot of platelet transfusions and blood transfusions.

She was started on asciminib, but we had to really use a suboptimal dose because of her recurrent cytopenias. And now we’re trying to get all of her vital organ testing so that she can proceed to an allogeneic stem cell transplant. She’s also a smoker, and so we had to have those discussions about smoking cessation, and that is a real problem for some patients. And so we always have this discussion about did you stop smoking, and she always says yes, but you can smell the cigarettes — you can smell it on her. So I’m hoping that she can pass her pulmonary function tests.

So we know that chronic myelogenous leukemia was a major — these TKIs were a major breakthrough in treatment and survival, and I think sometimes it’s not taken seriously, and that it’s potentially deadly if it’s not treated appropriately. I think that’s what we see in our institution, which is really sad. We have very effective therapy, and patients need to be treated and the milestones followed, and I guess that’s the sad part, to me, is that sometimes patients in certain psychosocial areas aren’t able to really get the therapy that they need and meet those milestones.

So we do have these disparities that exist. In countries where patients don’t have access to TKIs you don’t see the same survival advantages, and you do need expert guidance in the treatment and management of CML, with specific types of CML, and access to clinical trials.

DR LOVE: So CML became the poster child for “curing” cancer, but we talked in the past about functional cure, patients are going to be on treatment for the rest of their lives, dealing oftentimes with some side effects. But the other end of cure is actually getting rid of the disease, getting it to a low enough point that the body’s immune system can handle it. We’re going to talk in a second about the attempt to stop therapy in patients who we think are cured.

But just getting back to practical use, Neil, of asciminib. Can you talk about how the patients take the drug, that it’s supposed to be taken fasting, and how you encourage adherence?

DR SHAH: Yeah. So it can be prescribed — for the majority of patients, who do not have this T315i mutation, the dose is either 40 mg twice daily on an empty stomach or 80 mg once daily on an empty stomach. And echoing one of the earlier comments, I think twice daily on an empty stomach is a lot to ask, so I only prescribe it once daily on an empty stomach. And I think that’s very doable. I just tell patients if you wake up — it's no food 2 hours before, until 1 hour after. So if you wake up, and you take it first thing, and you wait an hour before you eat or have any coffee or anything, then that’s fine. Most patients can adapt to that. And so that’s how I basically recommend the patients take it.

Feasibility of TKI Discontinuation for Patients with Sustained Response to Treatment

DR LOVE: So let’s talk about attempting to stop therapy. The clinical scenario we’re talking about is the patient who’s been on a first-line tyrosine kinase inhibitor for 3 years, and the issue of being able to discontinue therapy, no cost involved in that situation, at least for medications, and how we can achieve that and the likelihood of achieving it. So Neil, can you talk about how this actually plays out in clinical practice and the trials that support this strategy?

DR SHAH: Yeah, sure. So it was really — obviously the outcomes that we’ve talked about, the superior outcomes we’ve achieved with these, has just been enormous, has been extremely gratifying. Of course, the ability to potentially stop treatment is taking it even one step further, and for many patients this is an important treatment goal, to ideally get off of treatment for one of a variety of reasons.

But first I just want to talk about how we follow patients typically on TKI therapy. So after initiating TKI therapy it is important, as mentioned, to get frequent CBC monitoring to make sure there are no early cytopenias. Early cytopenias are not unexpected. You can get them with any drug. It’s really a sign of activity of the drug against the target and rapid disease burden reduction.

And then I usually see patients after about a month to make sure that they’re tolerating it, to answer any other questions that may have come up. And then after that, basically 3 months after starting treatment, and every 3 months thereafter, and office visit with a CBC/diff, a metabolic panel and a quantitative PCR is typically how I follow people.

NCCN has these guidelines for treatment milestone response, and the green is where you want to be, ideally. And we alluded to this, and you have access to this in terms of these response milestones, they are time dependent, and so you don’t want to necessarily wait forever to be in the green level.

So what really opened our eyes was a study out of France many years ago, where they were actually brave enough to take people who had been responding extremely well to imatinib, meaning that they had no detectable disease even by PCR, which is the most sensitive test that we have, and they had been in this undetectable state for at least 2 years, and then they underwent a cessation of therapy with very careful molecular monitoring. Those downward-pointing yellow arrows refer to how frequently the molecular testing was occurring. And they basically were going to go back on treatment at the first sign of any detectable CML.

And what was observed is really kind of — was really very interesting and shown here. So this is basically survival without molecular recurrence. I want to be clear. These patients are all alive, but this is just those — if they have a detectable PCR, then they start falling off the curve. And you can see, unfortunately, in the first 6 months it’s a really rapid decline, right? A lot of patients are becoming detectable. However, there’s a plateau after that, and somewhere around 40% in this study going out for many years.

And we’ve seen this in numerous follow-up studies, and irrespective of whether the drug was imatinib or a second-generation drug. And you can see the number of patients in these various trials. So we’ve gotten a really amount of cumulative evidence. In general there were differences — there have been some differences in terms of how long patients needed to be in a deep molecular response and the duration of follow-up. But in general they found between a 40 and 60% likelihood of successfully stopping treatment, if patients had gotten to this level of response irrespective of which drug had been — that they had achieved that on.

And so the NCCN has these recommendations for consideration of discontinuation of therapy. And I want to be clear, this should always be driven by the patient, number 1. They should be eligible, and the eligibility are shown in the bottom. So chronic phase only, and they should have been on approved therapy for at least 3 years and in a stable at least 4-log reduction, or less than 0.01%, for at least 2 years, documented on at least 4 tests. And again, they should be monitored carefully every 2 months for the first year — 1 to 2 months for the first 6 months, and then 2 months for the remainder of the year, and then every 3 months thereafter. And at the first loss of major molecular response, meaning it rises above 0.1%, that’s an indication to go back on therapy.

And so I want to, again, highlight that this is never something I recommend for or against. I tell patients about the pros and cons, and I leave it up to them to decide. The majority of them do — are interested in doing this.

Another interesting thing that’s been found recently is that patients who are unsuccessful the first time, and they go back on treatment, they almost always go back into a really deep remission and maintain that. They can try a second time and be successful the second time around. And shown on the left is that curve. Studies are showing somewhere around 30 to 40% of the time patients can be successful a second time when they were unsuccessful the first time, so you get more than 1 swing at the pitch, if you will.

In terms of the reasons that patients cite. So bothersome side effects is a big one. Financial toxicity, again, there’s individual and there’s societal, concern about known and unknown late toxicities, and preference to avoid medications. But not everybody chooses to do this. Many patients say I’m okay with all of this.

There are some risks. There is TKI withdrawal syndrome, which is new musculoskeletal pain. This happens in about 25% of patients, and it was a little bit of a surprise. It’s rather peculiar, but it tends to be self-limiting for the most part.

We have to be clear that we don’t have long-term follow-up of stopping therapy. To date it’s less than 10 years, and that can be important, especially when you’re thinking about younger patients. More frequent testing can provoke anxiety in patients. And initially we didn’t see any progressive disease, but anecdotally in subsequent follow-up in real-world experience there have been a few cases, and so there’s not a zero risk that the patient will not have their disease become potentially more aggressive. Of course, we don’t know if that would have happened if they continued therapy, but of course we have to disclose this to patients.

And at the present time this is what we kind of think about the pie chart. So on the right you see the blue, there are about 50% of patients that never achieve the molecular response required. And then of those that do, on the left, the 50% that do, about half of those are successful, the yellow pie, and then the gray on the second attempt. But in general we think 65 to 70% of patients will require long-term therapy. So okay, yeah.

DR LOVE: So we’re going to move on in a second and talk about patients with progressive disease. But Mike, just to finish out on this idea of cure of CML and being able to stop therapy. A lot of times I think of younger people who want to conceive, for example, and the idea of being able to stop therapy. I’m curious whether you see older patients also interested in stopping therapy, and in particular right now is it your impression that asciminib is going to lead to the more — a greater likelihood of being able to stop therapy. I know that’s one of the major thoughts about this agent, in addition to the toxicity issues.

DR MAURO: Yeah. I mean, I’ll comment on asciminib first. I think it’s really encouraging that we can get to deeper remissions in a higher fraction of patients with little toxicity. And then the jury’s going to be out with regard to the cure fraction. Neil nicely summarized the fact that pretty consistently it’s a 50/50 shot, which sounds like we really did little research into it, but that’s thousands of patients over dozens of trials. If asciminib can improve on that, that would be a game changer, because then the financial equation changes. As you said, it’s only therapy for a few years rather than lifelong, et cetera.

Neil also summarized really nicely the prospect of TFR. I would say there’s 3 reasons, either you’re very motivated to do it, you’re having side effects that you’d like to get rid of, or there are side effects that could come, which could be dangerous or threatening to you. The first one, how motivated you are, is probably the biggest. There are some people who absolutely under no circumstances want to think about it, and some people who can’t wait. So it’s that spectrum, and I offer it, just as Neil does, as an option. I don’t endorse it or deny it. I say it’s something we can aspire to.

DR LOVE: So it’s interesting, tonight we’re going to be talking about chronic lymphocytic leukemia, and there, up until recently, the thought for a lot of therapies, particularly the Bruton tyrosine kinase inhibitors, were that people were going to have to take it indefinitely, just as we’re describing here. But tonight you’ll hear about time-limited therapy, 14 months of treatment, and they look at MRD, and then they’re done, so kind of following the same kind of approach that we just talked about here for CML.

Management of CP-CML After Failure of Initial Therapy

DR LOVE: So fortunately, most patients are able to be maintained either on therapy or, as we just talked about, being able to stop therapy. We asked Mike to review the patients who have disease progression for whatever reason, maybe lack of adherence, et cetera, and particularly patients who then develop mutations that make it difficult to treat. So Mike?

DR MAURO: So in the interest of time, I have a lot of slides, so have a chance to look at them on your — later on.

We’ve discussed a lot of the reasons why people could fail — or therapy would fail the patient. That was pointed out to me once. Never say the patient failed the patient; the therapy fails the patient.

And it can be via blood count resistance, PCR either persistence or lack of hitting a milestone, and Neil covered the NCCN Guidelines quite nicely.

So we really follow a pretty careful script. I’ll say that the deeper we get the more thoughtful we have to get about changing therapy in order to make a difference.

We also covered this — the fact that the NCCN guides us with regards to the question you have to ask. It does involve drug interactions, patient adherence. It’s not always that the patient is having trouble, and maybe they’re not taking it well, or they’re taking it beautifully, and the drugs not performing well enough. And there are specific mutations, which I’d have to say I’ve become a little bit more of an attention with the more newer approvals. We have newer drugs with more specific mutations that may be a little bit more frequent in the setting of resistance. So it’s really important to recognize that when there is a problem the mutation testing matters.

And just a couple bullet points. Intolerance is often mixed with resistance. If someone’s not responding to their treatment it may be because their dose has been reduced, or they’re really not able to take it as well as we’d hope they could, or they’ve had to switch, they had a gap. And you can see some of the rates are upwards — sometimes to 20, 30% of patients have to stop a drug because of side effects during a trial. So it’s good we have all these options. And that may be a little bit of a plug for why a drug with lower adverse effects might carry the day if it proves to be cost effective and safer.

We’ve researched a lot about how do we think about switching. On the top of this is just data that after imatinib, if you look at choosing one of the other second-generation drugs on the bottom there, the response rates are pretty similar, cytogenetic response. Survival is good but imperfect. And on the lower right is the comparison between maybe upgrading someone, in red is ponatinib versus all the other colors would be using another TKI, recycling one of the other drugs. So you don’t want to be shy about moving to new drug, but we have to be thoughtful and choose carefully.

There’s been a lot of discussion but never a comparison between this drug ponatinib, which we haven’t talked much about, and asciminib. Ponatinib is a very — again, a thoughtful drug development that was able to overcome this mutation, which was described nicely, the T315i mutation, and it was quite active in patients with multidrug resistance and intolerance. In the bottom, though, due to side effects, we’ve been trying to optimize ponatinib. And there was an attempt to see if we could use lower doses, starting lower or — and as you see, everyone is guided to reduce the dose. But we’re still held to using this full dose of ponatinib and managing what could be some of the adverse effects, which are described in this next slide.

And on the lower right is probably the take home here, that there’s a risk/reward with ponatinib. In blue is the risk of arterial occlusive events, that would be vascular events, and in red is the remission gain. And you can see that you gain a lot with the higher dose, 45 mg, but you also increase the risk of these arterial occlusive events, and they can be quite dangerous, so we have to be careful. So we really needed something better, and that’s how asciminib filled this initial role as a later-line drug.

This is the trial, and this was a comparison in people who had had 2 or more treatments. And some people thought it was a little unfair because bosutinib is a very good drug, but it has specific side effects. But at the time it was the only drug in this space, and so asciminib was compared to bosutinib in people who had had multiple lines of treatment.

And this is the likelihood of getting into a safe remission, a major molecular remission. In the green you can see asciminib outperformed bosutinib quite nicely here. And this trial really went to completion, and the later we went the better the response.

These are the likelihoods of people getting into deep pCR remissions. Again, with increasing time, you can see the gain. Now, bosutinib worked quite well in the patients who were able to take it. It also provided molecular remissions, but the fractions, and that was probably because a lot of people had challenging side effects with bosutinib leading to discontinuation.

So you can see that it jumps out in the middle of the slide, diarrhea, nausea for bosutinib are very frequent. Two thirds of patients will often have some GI issues and others. We’ve been talking about lowering the dose, and many patients wind up on lower doses. So there’s this mixture of intolerance and resistance that can really be a challenge for the patients, and where a drug with better side effects can really come in nicely.

Asciminib really is also active against T315i, so it was another drug in the toolbelt for use against this, not just ponatinib, and this is some of the data, including deep remissions.

And just a footnote, the dose is higher. Ilene mentioned that her patient was on a dose on trial that was higher, and some of the drugs in development still, and clearly asciminib, we use a different dose for a mutation than we do for patients without a mutation. But fortunately the side effects weren’t particularly different when we looked at the higher dose in these patients. So asciminib really filled a nice role early on, and we have to be quite thoughtful about these patients, though, because it’s complicated.

DR LOVE: It’s complicated, alright. Oncology’s complicated in general. And if you come on back here today at 12:15 you’ll see how complicated prostate cancer’s gotten recently, and extremely, extremely exciting. I want to thank the faculty for such a great job. Thank you for coming. Have a great morning.