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Expert Insights for Hematology/Oncology Pharmacists on Later-Generation TKIs as Frontline Therapy in Chronic-Phase CML

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Pharmacists: 1.00 contact hour (0.1 CEUs)

Released: May 13, 2025

Expiration: November 12, 2025

Dr Donald Moore (Atrium Health Levine Cancer Institute): All right, so thank you everyone for joining us today. I am going to kick things off by just discussing just a brief overview of chronic-phase CML. How we can individualize frontline therapy for patients, assess their risk, as well as how we monitor patients.

 

[00:19:03]

 

Chronic Myeloid Leukemia

 

Firstly, chronic myeloid leukemia or CML for short is a mild peripheral neoplasm that is going to be characterized by the presence of the Philadelphia chromosome. This is something that really occurs due to the translocation of chromosomes 9 and 22. When it happens is translocation results in the gene fusion of the BCR in the ABL genes to form the BCR::ABL oncogene. What this is going to lead to is a constitutively active tyrosine kinase that is going to lead to uncontrolled cellular proliferation. This is really going to be the hallmark and biologic feature of CML as well as what many of our drugs that we are going to use in this setting are really going to work to target against.

 

Now in the grand scheme of cancer, CML is not exactly the most common disease state and it has been found in the United States that there are roughly about 9300 new cases diagnosed annually with about 1300 deaths.

 

Now this is something that can occur in a very wide age spectrum, but otherwise has a median age diagnosis of about 6 to 7 years. Then very importantly, we may actually expect a near normal life expectancy when patients are taking modern CML therapies. When it comes to presentation, roughly about half to 60% of patients may actually present asymptomatically. Many patients may actually end up being an incidental finding on a routine CBC may eventually lead to the diagnosis of CML, but otherwise some patients may still present symptomatically and those may include fatigue, splenomegaly, unexplained weight loss, fever, and night sweats.

 

Now at least historically there has been really 3 phases of this disease state, including the chronic phase, which of course that is what we are going to be focusing on, that is by which the vast majority of patients will present as about 90% to 95% of patients presenting chronic phase CML. Then there is more advanced phase of the disease including accelerated and blast phase. There has been some other nomenclature out there to really divide these into chronic phase and advanced phase CML.

 

[00:21:02]

 

Goals of Therapy in Chronic-Phase CML

 

Our goals of therapy in CML when we are treating patients is to firstly and most importantly improve overall survival. Now, as I previously mentioned, luckily many patients will actually have a near normal life expectancy with treatment. Then otherwise we want to control the disease and that means trying to eliminate cells that contain that BCR::ABL oncogene, thereby leading to a remission.

 

We may also want to try to achieve what is called a treatment-free remission or TFR that will potentially be able to achieve for some patients, and we will talk through some of those aspects a little bit later on in the discussion.

 

Then otherwise we want to try to maintain patients in that chronic phase and try to prevent their disease progression to a more advanced phase such as accelerated or blast phase.

 

Then finally, with CML being a chronic disease may lead to long-term therapy and we really want to try to minimize toxicity to treatment, whether biologic toxicity or financial toxicity and try to improve their quality of life.

 

[00:22:04]

 

Prognostic Scoring Systems for Chronic-Phase CML

 

Now when it comes to prognosticating patients and their risk for disease progression, there is several different scoring systems out there that we can utilize and to really also help to guide first-line treatment. The 3 different scoring systems that we have are going to be Sokal, Hasford, and ELTS, which stands for the European Treatment Outcome Study Long-Term Survival.

 

They divide patients into 3 risk categories, low, intermediate, and high risk. Now, while these look like very complicated calculations, really you can find some different types of online calculators to plug in some of the numbers and variables to really help determine what the calculation is going to be between low, intermediate, and high risk.

 

These calculations take into account a few different clinical parameters including patient age, spleen size, platelet counts, and percentages of different myeloid cells in the peripheral blood including myeloblasts, basophils, and eosinophils.

 

[00:22:58]

 

Approved BCR::ABL1-Targeted Therapies for CML in Adults

 

All right, so let us get into talking about treatment. When it comes to first-line treatment of chronic-phase CML, we have several different treatment options and essentially they are all going to be tyrosine kinase inhibitors. They are going to be targeting BCR::ABL. We have got the first generation imatinib, second generation TKIs in dasatinib, nilotinib, bosutinib, and then general, we also have ponatinib, albeit not approved in the frontline setting. That is going to be the third generation TKI.

 

Then more recently we have got the approval of asciminib which is a little bit different than the other TKIs. This is also known as a STAMP inhibitor. STAMP stands for specifically targeting the ABL myristoyl pocket, also known as an allosteric TKI. All of these therapies, again except for ponatinib, all have indications in the frontline setting for chronic-phase CML. Then all of these drugs have an approval for a future line of therapy as well. It just also specifically call out for asciminib and ponatinib.

 

They also have an approval from the FDA for patients who have the T315I mutation–positive CML, which is a very deleterious mutation that does confer a poor prognosis.

 

Now when it comes to selection between all these different agents, there is a lot of different considerations that we are going to take into account and then we will talk through more in the next few slides. I think it is important to call us some of the differences in their dosing, how frequently they need to be taken, as well as if they need to be taken with or without food, as these are all oral therapies. Patient adherence to therapy is going to be very critical for long-term outcomes.

 

All of these for first-line treatment of chronic-phase CML, except for nilotinib, are all going to be once daily medications. Nilotinib is going to be a twice-daily dose.

 

Then I suppose also to call out for asciminib for the T315I mutation positive disease that is actually also going to be a twice daily dose as well as being a higher dose for those patients taking it for newly diagnosed disease.

 

Then when it comes to considerations of taking this with food, both imatinib and bosutinib need to be taken with food. Dasatinib and ponatinib are both neutral so they can be done with or without food. Then otherwise nilotinib, asciminib are recommended to be taken without food.

 

[00:25:09]

 

Chronic-Phase CML Treatment Selection

 

With these different treatment options, how do we really go about selecting therapy in the first-line setting for chronic-phase CML? I think 1 of the first things you really need to do is to risk stratify your patients into low vs intermediate or high risk. Really what it comes down to is that for low-risk patients, they can receive either first generation imatinib, second generation TKIs dasatinib vs nilotinib or now also have the option of asciminib. You will hear a lot more from Anthony later on the discussion on some of the data to support asciminib in this particular setting.

 

Then when it comes to intermediate or high risk disease, really we have all the same treatment options except imatinib in the setting is not going to be a preferred therapy.

 

Now with these different treatment options, we really need to take into account a multitude of other factors that are going to be a place where we could really try to personalize an individualized therapy for patients. We need to take into account factors such as patient age, comorbidities, the toxicity profile of a TKI and how that might interact with the patient's comorbidities, the potential for drug-drug interactions as these all have different drug interaction potentials and profiles.

 

Then we really need to consider the patient preference as well. Patients may have a preference vs specifically doing something once daily vs maybe twice daily. Maybe they might be a bit more neutral to that. They might have preferences if they want to take something with food vs without food vs not having to worry about it all together. Patient preference, the patient voice can be really important in here because of course their ability to stay adherent to therapy is going to be really important for them to be able to achieve good long-term outcomes.

 

You can go to the next slide please. Thank you.

 

[00:26:47]

 

CML Response Criteria

 

How we assess some of these outcomes is really we are looking at the response to treatment both hematologically, cytogenetically, and also molecularly. A complete hematologic response is going to be when patients are going to achieve a normalization of their peripheral blood cell counts, including their white blood cells and their platelets, as well as the lack of immature cells in the peripheral blood.

 

Now, cytogenetic response is going to be the measurement of the percentage of Philadelphia chromosome metaphases that may or may not be present. A complete cytogenetic response is when there are no Philadelphia chromosome positive metaphases present in the bone marrow peripheral blood.

 

Then a molecular response is going to be evaluating how many cells express that BCR::ABL oncogene and the bone marrow peripheral blood. An MMR or major molecular response is when there is less than or equal to 0.1% of cells that express BCR::ABL.

 

[00:27:42]

 

Prognosis Implication of Select Cytogenetic and Molecular Responses

 

Now these different response criteria have some significant prognostic implications associated with them. For a complete cytogenetic response achievement of that at 12 months has been 1 of the gold standard types of outcomes to look at here. That has been shown to be associated with an improvement in overall survival and progression-free survival. As you see here, 5-year OS rates are nearing about 97% when patients do achieve a complete cytogenetic response at 12 months vs 74% for those who do not.

 

Then achievement of MMR 12 months actually has not been consistently shown to be associated with improvement in overall survival, however, it has been shown to improve PFS and lead to lower rates of disease progression.

 

[00:28:26]

 

Response Rates and Survival With First/Second-Generation TKIs

 

I think that the other major thing to point out is if there is any real true difference in response rates and survival between our first generation and our second generation TKIs being that they all exist as treatment options together, particularly for patients with low risk disease and if there is any real differences between them from a response rate standpoint, particularly looking at more intermediate or high risk disease patients when the second-gen TKIs are all going to be really options up against each other.

 

Really what I think it comes down to across the board is whether imatinib, bosutinib, dasatinib or erlotinib, the achievement of complete cytogenic response at 12 months is relatively similar, somewhere in the order about 70% to 80% of patients with roughly half of those patients achieving a major molecular response at 1 year across all these different therapies and very similar rates of 5-year PFS and OS.

 

Something I think is really important to point out is that when it comes to the trials for these drugs, many of which are comparing second-gen up against imatinib. We actually do not have any head-to-head randomized control trials of second-gen TKIs up against each other. We do not have trials of bosutinib vs nilotinib or dasatinib vs nilotinib, etc.

 

[00:29:38]

 

Toxicity Spectrum of BCR::ABL1 Inhibitors in Adults

 

Now as I previously mentioned, it is going to be very important to really evaluate the toxicity profiles of each of these drugs up against each other, particularly up against comorbidities as we are trying to select out therapy for individual patients. I think this is a great place for us pharmacists to be able to weigh in. I think it is very important for us to understand what the classical toxicities and the class toxicities are going to be of these drugs.

 

Firstly with imatinib, some of the classical toxicities include edema, flu retention, myalgias, as well as some GI effects. With nilotinib, we need to be mindful about pancreatic enzyme increases, and then also cardiac toxicity with monitoring for QTc prolongation and watching EKGs periodically.

 

Dasatinib is classically associated with the development of plural and pericardial effusions. It may also lead to an increased risk of bleeding. With bosutinib, first thing that comes to my mind is going to be GI effects, diarrhea, nausea and vomiting as well as rash and elevated transaminase. Then with asciminib, we need to be mindful about pancreatic enzyme elevations with lipase and amylase.

 

Then finally ponatinib, again, while not a first-line treatment, something that a patient might need down the road, we need to be worried about cardiac toxicity such as hypertension, all the way to more severe things like arterial ischemia as well as pancreatic enzyme elevations as well.

 

Then really across the board for all of our anti-BCR::ABL TKIs we need to be watching for myelosuppression, transaminitis as well as changes in electrolytes.

 

[00:31:04]

 

Individualizing Targeted Therapy in Patients With CML With Specific History or Comorbidities

 

Now with selecting frontline BCR::ABL inhibitors, again, really considering the full picture of patients, their age, their medical history, comorbidities, really trying to match up their comorbidities up against some of these adverse event profiles and really trying to avoid overlapping toxicities with some of those preexisting medical conditions.

 

For patients who have coronary cerebral vascular or peripheral arterial disease, we would want to try to avoid nilotinib or ponatinib where we can do to overlapping cardiac toxicities. For patients with underlying hepatic impairment, we would want to consider a dose reduction of bosutinib down to 200 mg once day if we are going to go with that agent.

 

For patients with preexisting pulmonary arterial hypertension, we would want to avoid dasatinib as it has also been associated with development of pulmonary hypertension. With patients who have risk for pleural effusions such as lung disorders, uncontrolled hypertension, we may also want try to avoid dasatinib where we can there as well. Then for patients who are at a risk for hemorrhagic complications such as being on anticoagulation, or antiplatelets, if we could, dasatinib may want to be avoided there as well.

 

Then for patients with baseline renal impairment, lower creatinine clearance, we might want to be a little more cautious with using bosutinib and maybe potentially dose reduce imatinib if we need to go with that too. Then for patients with uncontrolled diabetes, perhaps trying to avoid or be very cautious with nilotinib as that agent can also cause increase in hyperglycemia, which could of course worsen a patient's diabetes.

 

Then for any patient with a history of pancreatitis or a high risk for it, we want to have very careful monitoring with ponatinib or asciminib. We have to go with 1 of those therapies.

 

[00:32:40]

 

Let’s Revisit Some Questions

 

All right, so now let us jump back into our patient case and revisit some of those questions that we talked about in the very beginning.

 

[00:32:47]

 

Patient Case

 

RJ is, as you may recall, a 67-year-old patient referred to your hematology clinic for newly diagnosed CML, high risk score by the Sokal score. His past medical history is significant for poorly controlled type 2 diabetes. Current medications include metformin and insulin glargine.

 

[00:33:04]

 

Posttest 1

 

Which of the following medications should be initiated for chronic phase CML?

 

A. Asciminib;

 

B. Imatinib;

 

C. Nilotinib; or

 

D. Ponatinib;

 

All right, so let us look at our answers. All right, so we still have a lot of imatinib here and we will talk through maybe a little bit more here, but we got about 20% who went with asciminib. Let us move on to our rationale.

 

[00:33:33]

 

Posttest 1: Rationale

 

Between these 3 different options: asciminib, imatinib, and nilotinib would all be indicated for first-line treatment of chronic-phase CML. Now with this patient having a higher risk disease, imatinib would not be a preferred first-line treatment option. Then for really for high-risk disease, we want to consider a second-gen TKI or asciminib. For this patient, their comorbidities we may want to try to avoid nilotinib. May not be an ideal candidate due to the fact they have uncontrolled diabetes.

 

Ponatinib is not an approved first-line therapy so we want to avoid that. Asciminib otherwise would be potentially indicated for it this patient as it does have now a recent indication for first-line treatment of chronic-phase CML.

 

[00:34:18]

 

Posttest 2

 

All right, so now that we are going to move RJ to starting on asciminib among the different approved BCR::ABL1 inhibitors, which of the following is a unique adverse event associated with asciminib that we may want to counsel them on?

 

A. Arterial ischemia;

 

B. Edema and fluid retention;

 

C. Lipase and amyloid elevations or;

 

D. Pleural or pericardial infusions;

 

All right, let us look at our answers. All right, so excellent job. I see most got lipase and amyloid elevations, which is absolutely correct.

 

[00:34:52]

 

Posttest 2: Rationale

 

For asciminib, one of the main things to watch out for is going to be pancreatic enzyme elevations. Edema/fluid retention, B, that is going to be mostly imatinib. A. Arterial ischemia is going to be some of the classically associated with ponatinib. Then for pleural/pericardial effusion, that is certainly with dasatinib that we need to be worried about with that.

 

[00:35:15]

 

Pharmacist Role: Monitoring Responses to CP-CML Therapy

 

All right, so now moving on. It is my distinct pleasure to hand this presentation over to Karen Fancher, who is going to talk about monitoring responses in chronic-phase CML.

 

Dr Karen Fancher (Duquesne University School of Pharmacy): All right, thanks so much Don for the great discussion. It is my privilege today to talk about some of the monitoring responses that we will use to determine if the patient has met the milestones that Don mentioned or if it is time to switch to another therapy.

 

[00:35:40]

 

Let’s Start With a Question

 

I also have a question to lead off this part of the discussion.

 

[00:35:43]

 

Patient Case

 

Another patient case. You are seeing a patient, TR, who has chronic-phase CML. After 3 months of therapy with bosutinib, the patient had a significant reduction in their white blood cell count and an improvement in their splenomegaly and their BCR::ABL comes back at 5%.

 

[00:36:02]:

 

Pretest 3

 

Given this information, what is the most appropriate course of action for the patient's CML therapy? Is it:

 

A. Continue therapy with bosutinib;

 

B. Increase the dose of bosutinib;

 

C. Stop bosutinib and change to ponatinib; or

 

D. Stop bosutinib and refer for an allogeneic stem cell transplant.

 

We are going to reveal the answer as we go through some of the information here. I have to say I think that is a hard question to answer without some of the tables I am about to show you. We can go to the next slide.

 

[00:36:41]

 

Monitoring CML

 

As pharmacists, we usually come along when the patient has been already diagnosed with CML, but I think it is important to understand how that process occurs. Historically, we would do a bone marrow examination to look for a percentage of blasts and confirm the presence of the Philadelphia chromosome through cytogenetic analysis.

 

We still do that, but at diagnosis. Historically, we would do a repeat bone marrow biopsy several times. You can see here at 3, 6, and 12 months. In clinical practice, we have much more sophisticated testing now. Those historical bone marrow biopsy over and over repeat are probably not necessary.

 

We can use a FISH test, so fluorescent in situ hybridization to detect the BCR::ABL rearrangements as we have listed here. While this is a great screening tool to detect the presence of that, it does not really give us information about how much is present. Again, in current clinical practice, we could use it for monitoring, but it is not preferred unless we are in a very resource constrained setting.

 

What really drives our decision-making process in current practice is molecular monitoring.

 

[00:37:53]

 

Molecular Monitoring Techniques

 

Now talking a little more about the molecular monitoring techniques. We use what is called a polymerase chain reaction to detect messenger RNA levels extracted from the peripheral blood. Again, a bone marrow biopsy would not be required to get this piece of data.

 

The gold standard would be a specific type of PCR called quantitative reverse transcription PCR, and this would be where we use what is called the international scale. We look at those transcript levels as a quantity and that is compared to a controlled gene and ultimately reported as an international scale.

 

We can use this BCR::ABL messenger RNA level as a surrogate for disease burden, the same way we would use a measurement on a CT scan for a patient with a solid tumor. Good news for us that MRA level also can be used to correlate the patient's clinical outcomes. We can use that as a marker of long-term prognosis.

 

We can use this level to stratify patients in terms of how good or deep their response is as opposed to other hematologic responses that really only tell us if the blood counts have decreased.

 

[00:39:05]

 

Emerging Molecular Monitoring Techniques

 

There are several emerging molecular monitoring techniques which are beyond what we are talking about here today. Again, if you are at a practice center that uses quite a bit of the high tech monitoring parameters, you may see these. These would be things like a nested PCR, which has even greater sensitivity than what we are using in most clinical practices. There is a multiplex PCR, which can be used to diagnose and detect atypical transcripts. For the rare patient with CML who is not Philadelphia chromosome positive.

 

Finally, there are digital and DNA-based PCRs that are not broadly available. These may be helpful when you have a patient with a very low level of disease or if we need to identify specific point mutations in that ABL domain.

 

[00:39:54]

 

Current CML Monitoring Recommendations

 

This is probably what we would see more of as pharmacists. When do we do these tests and when do we repeat them? At diagnosis, all patients should have a bone marrow biopsy done to look at cytogenetics. Again, we probably do not need to do another bone marrow biopsy unless certain milestones have not been achieved, which I will show you in the upcoming slides.

 

If we suspect that the patient is losing their response and whether that is a hematologic response, a cytogenetic response, or it is molecular response. If any of those are suspected of being lost, we may consider repeating a bone marrow biopsy.

 

As we mentioned, the gold standard test right now would be a quantitative PCR using that international scale, that should be done at diagnosis but also repeated every 3 months for the first year, in some cases up to 2 years, and then less frequently thereafter. This could be repeated more frequently again if we suspect that the patient is losing their response.

 

Patients should also have routine hematologic testing such as a CBC, every 1 to 2 weeks for the first several months. Again, if we suspect that the patient is having side effects from the drug therapy that we mentioned such as cytopenias.

 

[00:41:07]

 

CML: TKI Sensitivity and When to Consider Changing Therapy

 

This is a simple chart to tell us when we may need to consider changing therapy. You can see here we would be doing those BCR::ABLs through the PCR on the international scale. We should be doing that every 3, 6, and 12 months. Depending on what the level is, we may need to consider possible resistance and changing to an alternative agent. You can see here we break that down into greater than 10%, 1% to 10%, 0.1% to 1%, and less than 0.1%.

 

Obviously, we would like to see everything on the far right of this graph where the disease is sensitive and we can continue current therapy.

 

[00:41:53]

 

Mutational Analysis of the BCR::ABL1 Kinase Domain

 

This is the more complicated version of that table. This is color coded according to the NCCN guidelines and, again, this would let us know if we can continue therapy as the patient had been taking it if we need to consider changing or if we absolutely should stop therapy. Again, we should be checking the BCR::ABL by the international scale at 3 months, 6 months, and 12 months.

 

Starting on the far right, if our level is 0.1% or less, everything is in green. We can continue without any changes. If the BCR::ABL level is between 0.1% and 1%, in most cases we can continue on the same therapy. However, if the patient is at the 12-month mark, we may consider a change in therapy, and this would be dependent upon the patient's goals, whether they are interested in a treatment-free remission or if they are fine with continuing therapy somewhat indefinitely.

 

You can see as we move towards the left, now we are starting to see some warning signs with orange and yellow, and in red that would be to stop therapy or switch therapy to another agent. Again, as an example, if we had a patient with a level of greater than 10% at the 6-month mark, we strongly suggest or suspect that therapy is not appropriate and should be switched to another agent.

 

As pharmacists, I want to call out also the row that says at all time points we should be assessing adherence as well as the possibility of drug-drug interactions. If those have been ruled out, then we can consider changing or switching to another therapy. Again, we should be asking those questions at every visit.

 

[00:43:42]

 

Mutational Analysis of the BCR::ABL1 Kinase Domain

 

All right, so you may be thinking when do we need to do a mutational analysis? If it had fallen into that red category that I showed you there, the patient may have developed a resistance mutation.

 

Resistance mutations do not typically occur in a primary setting. Those are usually developed over time and we get into a secondary resistance. If we suspect resistance, we could test with a mutational analysis. Again, if that response that I had expected at the time has not been achieved.

 

Then depending on what those results show me, I could actually match a more appropriate drug to that patient. For example, as Don called out, the deleterious mutation I am worried about most is called T315I. If that mutation had developed, it would not be appropriate to use bosutinib, dasatinib, or nilotinib and perhaps asciminib or ponatinib would be a more appropriate choice. Depending on the results, we could tailor the therapy most appropriately.

 

[00:44:45]

 

Clinical Care Options CML Monitoring Tool

 

We did want to point out that CCO has an excellent monitoring tool that can help you through some of the thought processes we just went over. You can use the QR code shown here on the slide. There is a decision-making tool that can help you with and you can also contact for more information, if that is of interest. Be sure to check that out.

 

[00:45:07]

 

Let’s Revisit Our Earlier Question

 

All right, so returning to our earlier question.

 

[00:45:13]

 

Patient Case

 

Our patient has chronic-phase CML, and after 3 months of therapy with bosutinib had a significant reduction in their white blood cell count and improvement in splenomegaly and the BCR::ABL was done and comes back at 5%.

 

[00:45:28]

 

Posttest 3

 

At this time, what is the most appropriate course of action with the patient's therapy?

 

A. Continue therapy;

 

B. Increase the dose;

 

C. Stop bosutinib, and change to ponatinib; or

 

D. Stop bosutinib and refer for a stem cell transplant;

 

All right, let us take a look. All right, excellent. Again, hard to answer this question without having the table in front of you, but this patient has met the milestone for the 3-month mark. At that point, we would like to see the BCR::ABL between 1% and 10%. This patient had 5%, so perfect. This patient should continue with bosutinib without changes.

 

[00:46:12]

 

Posttest 3: Rationale

 

Here we have the rationale there as I said. This patient is at their goal milestone. It does not need a change. We would again, assess adherence and look at drug interactions, but we could continue on the same agent.

 

[00:46:28]

 

Integrating New Frontline Data Into CP-CML Clinical Practice

 

At this time I get to hand things over to Dr Anthony Perissinotti to talk about some of the new frontline data.

 

Dr Anthony Perissinotti (University of Michigan Health System): Great, thank you. Hi, everybody. I was set up perfectly by Don and Karen today to talk about the frontline data, but I am also going to talk a lot about newer asciminib data as well.

 

[00:46:52]

 

Case Discussion: 56-Yr-Old Man With CP-CML

 

Similar to the other presenters, we will start off with a case. You have a 56-year-old that was diagnosed with CML. They know nothing about TKIs, has a very active lifestyle, minimal comorbidities to none, and has a demanding career.

 

[00:47:07]

 

Poll 3

 

Question for you all, which of the following TKIs would you recommend as the most appropriate for this therapy?

 

A. Asciminib;

 

B. Bosutinib;

 

C. Dasatinib;

 

D. Imatinib;

 

E. Nilotinib;

 

F. Ponatinib;

 

All right, thank you.

 

[00:47:37]

 

Pretest 4

 

Pretest question, which of the following was reported in the 96-week update of results from the randomized controlled trial to ASC4FIRST of oral asciminib vs investigator-selected TKI?

 

A. Asciminib was associated with significant improvements in MMR at week 96;

 

B. Asciminib was associated with comparable MR4 and MR 4.5;

 

C. Asciminib was associated with higher frequency of AEs leading to discontinuation; or

 

D. Lastly, common AEs associated with asciminib included periorbital/facial edema.

 

[00:48:25]

 

Asciminib: Mechanism of Action

 

Throughout this presentation we have thrown around a couple of different new terms: STAMP, myristoyl, allosteric site. What does all this mean? I think as pharmacists it is really important to understand the mechanism as opposed to just being able to regurgitate off fancy terms.

 

Normally under non-malignant conditions, ABL is shut off because of engagement within that myristoyl pocket. Well, when you have that translocation of BCR::ABL, that myristoyl pocket closes and can no longer be engaged. Ultimately, you then have a constituently active ABL and so you get CML.

 

We can then take asciminib and put it inside that myristoyl pocket and then it inhibits ABL again and shuts down BCR::ABL. That is acting at the allosteric site, and this is important for a couple of reasons.

 

One, it is a very different place than the ATP binding pocket. From a resistance perspective, there will be less cross resistance because you are literally in a different pocket than the other TKIs that we have. The cross resistance occurs both ways. You could have a patient that is resistant to an ABL pocket TKI that will not have resistance to asciminib, and vice versa. You could have resistance to asciminib, but it is in the allosteric site that therefore you will not have resistance to your other TKIs. That is 1 importance.

 

The other importance is the allosteric site is not the active catalytic site and therefore pharmacologically, when we are developing drugs, you can actually make drugs much, much, much more selective to that as opposed to the active ATP binding pocket. What that means is you can have less side effects from this medication as well because it will have less promiscuity. For example, dasatinib hits over 200 different kinases, whereas asciminib is very, very selective to just that myristoyl binding site.

 

[00:50:40]

 

What Are the Unmet Needs?

 

The big question for all of us to answer is, okay, we already have 5 TKIs on the market, do we really need another one? CML outcomes are phenomenal and I would argue, and actually it is not even an argument, it is an absolute yes, we absolutely do need a sixth TKI. The reason being is I started using asciminib back when it was called ABL001, and patients that were multiply refractory and have exhausted all of their TKIs.

 

If it was not for asciminib, unfortunately that patient would have passed away. Thankfully with asciminib, now I have an option for that patient. After that, it was, well, what about the patients with T315I mutations that are not candidates for ponatinib because ponatinib can be quite toxic? There is a high incidence of thrombotic events.

 

Now, I have 2 options to think about for my patients with T315I mutations. Now more recently I am going to show you some data where we are starting to move asciminib even earlier on. First, it will be compared to other second generation in TKIs after patients have failed other TKIs. Also I will show you some frontline data that takes a look at asciminib compared to the other TKIs in the frontline setting.

 

[00:51:53]

 

ASC4FIRST: Asciminib vs IS-TKI for Newly Diagnosed Ph+ CM-CML (96-Wk Update)

 

That study was the ASC4FIRST study, which I asked a pretest question about. This was a randomized controlled trial of patients with low, intermediate, or high risk and they are randomized to asciminib or investigator-selected TKI. What that meant was before randomization, the investigators had to decide was my patient appropriate for imatinib or a second generation? They were stratified based off of that.

 

The primary endpoint was MMR at week 48. Here I am showing you the most up-to-date data where beyond week 48, we now have data up to week 96.

 

[00:52:30]

 

ASC4FIRST 96-Wk Update: Baseline Characteristics

 

These are the baseline characteristics here, and this table is pretty busy. I want to orient you to how to read this. The first section of the column is asciminib, and then patients were stratified by the imatinib cohort here. These are patients that got asciminib but were stratified in the imatinib vs if you look over here, this is what you should be comparing imatinib to imatinib.

 

Also here is your second-generation comparing this column to this column over here. Okay, so now that I have oriented you to that, you can see that the baseline characteristics are very well balanced between these.

 

[00:53:17]

 

ASC4FIRST 96-Wk Update: Patient Disposition

 

Majority of patients have lower intermediate risk. Again, the reason why I wanted you to really be oriented to here is because here is some very important information. Some of the results. More patients discontinued therapy if they received imatinib or even a second generation TKI. The number 1 reason why patients discontinued therapy in the imatinib arm was unsatisfactory effect followed by adverse effect. Vs the second generation the most common reason for discontinuing was due to adverse effect.

 

You can see when you compare the 2, patients discontinued asciminib less likely because of both cumulatively not having an unsatisfactory event and also not having as many adverse events.

 

[00:54:11]

 

ASC4FIRST 96-Wk Update: Molecular Responses With Asciminib vs IS-TKIs

 

Here is the MMR at 96 weeks, and again in the overall cohort you can see an improvement with asciminib. Now one could argue a lot of this is being driven by the inferior TKI imatinib. We know that imatinib is not as potent as the second generations, but then if you look at the far column, we cannot say this statistically, but conservatively.

 

If I want to say conservatively and I do not want to anger our statisticians or the purists who look at literature, I would say that asciminib is at least equal to the second gens. It was not just primarily being driven by imatinib here. Then if you look at MR4, MR 4.5, the same trend occurs here too.

 

[00:54:58]

 

ASC4FIRST 96-Wk Update: Cumulative Incidence of MMR, MR4 and MR4.5

 

I think it is probably easier to look at the actual visuals of the Kaplan-Meier curves here. You can see asciminib vs all TKIs early separation essentially saying that patients have faster and also deeper responses and that responses are quite durable as well.

 

Yes, a lot of this is being driven by imatinib, but you can also see those separations with a second generation. Again, statistically we cannot say that it is an improvement compared to our second gens, but you can at least see that it is not worse than the second generation.

 

Let us just be very conservative and say from an efficacy standpoint, asciminib is equal to our second generations. Again, I am being very conservative there.

 

[00:55:46]

 

ASC4FIRST 96-Wk Update: MMR by Subgroup

 

When you look at the subgroup analysis, there was not necessarily any subgroup that deviated from this. All subgroups benefited from asciminib. In the patient population that really benefited, this is what Don showed earlier, was patients with high risk disease. Look at that. A 40% relative improvement in our high risk patients, and so this speaks to our current practice of yes, intermediate high risk patients do get more bang for your buck with our later generation TKIs.

 

Furthermore, I think you could also make argument that even an improvement of 15% for our low risk patients is also quite impressive as well. That is the subgroup analysis.

 

[00:56:35]

 

ASC4FIRST 96-Wk Update: Safety and Tolerability

 

Let us take a look at some of the adverse effects. When you look at grade 3 adverse effects, again, let us be conservative and say that they were somewhat equal with imatinib, but you can take a look at the second generations. There were more grade 3 adverse effects with the second generation. Putting this all together, what would I conclude here is, yes, asciminib is more efficacious than imatinib. We know that. Our second gens are more effective.

 

Then the second thing is that asciminib is equally effective as our second generations, but better tolerated than our second generations. Again, I am trying to be fair and balanced and very conservative with some of my conclusions here.

 

Looking across some of the adverse effects, nothing really stands out here. These are things that we would expect with imatinib. These are things that we would expect with our second generations and nothing that is glaring in the asciminib arm.

 

[00:57:35]

 

ASC4FIRST 96-Wk Update: Hematologic and Gastrointestinal AEs

 

Furthermore, when you take a look at some of the constitutional symptoms and laboratory AEs, as Don mentioned earlier, we do have to think about increased amylase and lipase. We did still see that with asciminib, but overall the overall picture is that asciminib is better tolerated than our second gens and there are still low grade toxicities of imatinib that can lead to discontinuation more frequently like periorbital edema that we have to be thinking about as well.

 

Next slide here.

 

[00:58:14]

 

Posttest 4

 

Back to our post-assessment question here, so which of the following was reported in the 96 week update of results from the randomized phase III ASC4FIRST? Was it?

 

A. Asciminib was associated with significant improvements in MMR at week 96;

 

B. Asciminib was associated with comparable MR4 and 4.5 to conventional TKIs;

 

C. Asciminib was associated with higher frequencies of AEs leading to discontinuation; or

 

D. Lastly, common AEs associated with asciminib included periorbital/face edema;

 

[00:59:18]

 

Posttest 4: Rationale

 

All right. Okay, so a little bit of a split here between the first and the second answer. Ultimately, the correct answer is A. We definitely saw significance improvements in MMR. Now I think where we might be getting tripped up is MR4 and MR 4.5 compared to the second gens. Although there is slight separation, you cannot really say that there is a difference, but there was a difference with imatinib. We cannot say that they are comparable. I do think that asciminib does lead to deeper remissions when you look at the whole cohort.

 

[00:59:55]

 

What HCPs Need to See for First-line Adoption

 

Okay, so what do we need to now start using asciminib for every single patient? Obviously, we would love to see overall survival data, but that is not going to happen. I think we have to be realistic here. We are not going to improve overall survival. We have excellent options on relapse. Patients thankfully will likely die from other things than CML.

 

The other things that we need to look at is quality of life. We need to do proper quality of life assessments. We need PROs. We need our patient data to tell us, "Do I feel better on medication A vs medication B?" If we have robust data, I do think that would help with choosing asciminib. That would be some great data to really have. It cannot be, "Oh, quality of life is comparable." No, it needs to be better.

 

The other things that would be helpful to change practices, do I see more patients in very deep remissions to the point that they end up coming off of their therapy and end up dying from other diseases than CML and hence that would be a functional cure. I need to see more patients with an MR4, MR 4.5 after several years stopping therapy. I need to see more patients stopping therapy and being off therapy, more often than our second generations to say, "Yes, this is slam dunk, need to change practice."

 

Lastly, putting this all together, we need to look at cost-effective analysis. Now it cannot be just the drug, which the drugs are super expensive. Let us say that the drug only costs $100,000 a year. There is 10,000 new cases of CML every single year that is $1 billion and these drugs cost more than a $100,000 a year. It is probably $2 billion to $3 billion.

 

Now, yes, it is the drug cost, but then we also have to think, "How many patients am I getting off therapy?" Those are going to be a teeter-totter. I need strong data to tell me that I am doing things in a cost-effective manner.

 

[01:01:55]

 

ASCEMBL: Asciminib bs Bosutinib for Previously Treated Chronic-Phase CML

 

That was the frontline. What about if you had a patient that was started on imatinib or dasatinib and is not meeting their milestone or they are failing therapy? Do we have any data for that patient population? The answer is yes. This was the ASCEMBL study that compared asciminib vs bosutinib in a randomized controlled trial. The primary endpoint was MMR at week 24.

 

[01:02:15]

 

ASCEMBL: Response Rates

 

You can see here that at week 24, week 96, week 156, we see much deeper and faster responses with asciminib compared to bosutinib.

 

[01:02:34]

 

ASCEND-CML: Study of Asciminib for Newly Diagnosed CP-CML

 

This is the ASCEND trial. This is another prospective trial in the frontline setting where patients start on asciminib. If they do not meet Karen's milestones, we either dose increase or we will add on another TKI as well.

 

[01:02:51]

 

ASCEND-CML: Baseline Characteristics

 

Here is the baseline characteristics.

 

[01:02:55]

 

ASCEND-CML: Summary of Molecular Responses

 

Not surprising here. It appears as though MR4, MR5 are higher than what we historically would appreciate with these dose modifications and additions. We really need a comparator arm. We need to compare it to the standard of care to know exactly what this actually means. I think this is a good step in the right direction.

 

[01:03:20]

 

ASCEND-CML: Safety

 

Toxicity. The bottom line is if you add more than 1 drug, if you are increasing the drugs' concentrations, you are going to likely see more toxicities. We need to be thinking about the toxicities quality of life and not just are we achieving better MR4, MR 4.5?

 

[01:03:45]

 

ASCEND-CML: Patients With Suboptimal Response

 

All right, so what happened to some of these patients? Among the patients without an MMR, there were 10 of them. Eight of them did a dose escalation. Seven of them achieved MMR, middle column. Patients without an MR4 at 18 months, 20 received dose escalation. Eight of them ended up achieving MR4. Then in the last column, only 3 patients ended up on combination therapy.

 

[01:04:15]

 

ASCEND-CML: Resistance

 

This slide illustrates some of the cross resistance or the lack of cross resistance. There certainly is cross resistance, but anytime you have mutations within the myristoyl pocket or even the seed loop, that is not going to confer resistance to our other TKI. We actually can salvage patients with things like dasatinib. Challenging ones are compound mutations like a T3115I plus M244B, but we also have ponatinib for those patients. The long story short of this is if a patient does fail asciminib and develop resistance, many patients can be salvaged with additional TKIs.

 

[01:05:02]

 

Phase I Study of Asciminib in Previously Treated CML With T315I Mutation

 

Don, already talked about this. Super important when you are using asciminib for a patient with T315I, you have to use the high dose. T315I creates a confirmational change where it is very hard for asciminib to get into that myristoyl pocket. It just bounces out. You need high concentrations to shove it inside of that little pocket there.

 

[01:05:29]

 

ASCMORE 96-Wk Follow-up: Asciminib Add-on + Imatinib vs Imatinib vs Nilotinib

 

Lastly, there is some data the ASC4MORE/FIRST. These are patients that were on imatinib. Did not achieve their milestones. They added asciminib or they switched to nilotinib. Intriguing data. Good to understand how to combine therapies, but ultimately we need full out randomized controlled trials to know should we really be combining therapies and talk about costs? You are talking $400,000 a year when we are combining things.

 

[01:05:56]

 

Asciminib Overview

 

Don talked a lot about asciminib and all the things you should think about the dosing.

 

[01:06:02]

 

Asciminib Drug Interactions

 

There are drug interactions and things that you would be surprised about. Pull up the PI next time you use asciminib. Some things that you probably did not expect, like do not use rosuvastatin or atorvastatin. Think about some of the things inside of the PI and pull it up next time you use asciminib just so that we are safe with our patients.

 

[01:06:25]:

 

Panel Discussion

 

Lastly, this brings up a nice discussion that Don is going to lead of how we can integrate pharmacists and be multidisciplinary with all of our TKIs in CML.

 

Dr Moore: All right, yeah, it is a great discussion everybody. I think it was bringing us the 3 of us together to talk through maybe some of this stuff and how we can really integrate it for patients. First question for Karen. What barriers do you think exist and really in trying to incorporate patient goals with their guideline risk assessments, and really our monitoring strategies when we have patients for being treated for chronic-phase CML?

 

Dr Fancher: Sure. My patient population is in the community and I see a lot more elderly patients. I think my observation is that we do not offer the patient or bring a discussion forward about this treatment-free remission that we have all been hinting at about the potential ability to stop or hold therapy for some length of time.

 

In my conversations, or at least the ones I have been part of, I do not feel that we bring that forward enough to the patient right up front. This might be a goal. I think we are so interested in getting patients on therapy that we do not really bring up the fact that maybe there is the possibility that we could have sometime get you off.

 

Of course that would require more intense monitoring and some of the monitoring parameters that I mentioned here. I think because of my patient population, we do not have that in the front of our minds and maybe we could bring that up a little sooner in the conversation with our patients.

 

Dr Moore: Excellent. For our next question here, I know we are all pharmacists here. We have been talking a lot about peripherally what we can do for patients and what our role might be and when we are treating chronic-phase CML. Anthony, how do you think that hematology pharmacists can really contribute to multidisciplinary teams to optimize treatment plans for patients with chronic-phase CML?

 

Dr Perissinotti: Yeah, I think the obvious pharmacist things are we need to make sure patients are educated. We need to make sure patients are compliant. These are just traditional things that everyone in the audience already knows.

 

Let me propose something that is less conventional. I think the thing that I see our pharmacists do incredibly well is they are literally the quarterback for everything. I will give you an example. At our center, we have about 3 or 4 different leukemia doctors that treat CML. The last thing I want to do is to have disproportionate care between my patients coming to my same center. I do not want one physician treating one way, one treating this way. I want to have a standardized approach as possible.

 

Additionally, when new data come out, I want to be thinking about how do I incorporate this drug or how do I not? Do I even want to incorporate this drug? I think getting everybody in the room together, talking to other pharmacists to make sure that we all have a plan of how do we want to be treating frontline CML? Then getting everybody in the room and talking about how do we want to do this?

 

I think Karen brought up a barrier, and 1 of the barriers that she articulated is just misaligned treatment metrics. One physician might say, "Hey, my goal is MMR4. Others might say, "Mine is MMR4.5." It is like, "No, I do not care about any of that. I am not going to stop therapy. I just care about the side effects and whatnot." We need as a group to talk about, okay, what is our priority? Okay, what drug ends up achieving our priority the majority of the time? Just making sure that all of our thought's convergent. It is the pharmacist that is doing that.

 

Dr Moore: I love the unconventional approach to thinking of that. Really is something that I think a lot about now too, especially as we have widening treatment options across a lot of the other disease states we are all treating is how do we have some degree of equipoise and how we are approaching our giant cohorts of patients? Karen, I am interested in the same question for you too. Definitely being in the community, seeing multiple different disease states with different types of providers who may not just focusing on CML, what are some ways that you think that your role might be in these patients?

 

Dr Fancher: Yeah, I think 1 of my main roles is to actually bring some of these newer agents on people's radar. In the community, CML is going to be seen much less frequently than at a larger academic center. Occasionally, I feel like I am the one saying like, "Hey, what about this new one that just came out that we do not have as long-term data," as you made a really great point of saying, Anthony. "We do not have as great long-term data, but the short-term data is pretty impressive. Do we think there is a role here?"

 

I feel like a lot of times in the community, I am just a reminder of that data is available and just where do we think that fits in? I think in the community, old habits die hard. I sometimes feel like I have to push more than once, and that is okay. That is my role. Maybe we just are not as familiar with all of the options, given the fact that we have quite a few patients with multiple different diseases.

 

Dr Moore: Absolutely. I think definitely in the community, general medical hematology, oncology practice, they have got new data flying out all the time across all these different disease states. To be able to help them team up with something like this, where we have not had a new approval, a newly diagnosed brand new type of drug in a little while, bringing that to the forefront, I think that is a great role for us as pharmacists to be able to educate there. With that, we are going to move on. We have got a couple extra polling questions here for the audience.

 

[01:11:57]

 

Poll 4

 

Do you plan to make a practice change in patient care based on what you learned today?

 

A. Yes;

 

B. No or;

 

C. Uncertain;

 

Maybe. All right, let us see the results. Then for our next question, so we have got some people who said yes. Some who just thinking it over, but at least we got a few yeses.

 

[01:12:26]

 

Poll 5

 

Then please take a moment to enter at least 1 key change that you plan to make in your clinical practice based on this education. This is a short answer. For the audience, go ahead and type something in. I will give you a few seconds. Then otherwise, I think we have got a couple questions in the Q&A for us that the 3 of us can try to tackle. Going once. Going twice. All right, we can go ahead and move on from the poll.

 

[01:12:57]:

 

Q&A

 

Dr Moore: First question here. For patients with no other comorbidities or concomitant medications with newly diagnosed high-risk CML, how do you decide between a second gen TKI vs asciminib. Anthony, what is you thinking?

 

Dr Perissinotti: They are both right. I think when you look at the data, asciminib is better tolerated. It leads to at least similar deep remissions. You could argue maybe numerically better. On paper it is like, why are we even discussing this? This should be the new standard of care. No questions asked. It is not that easy. There are other things that we do think about cost.

 

Drugs like dasatinib will be generic soon. Imatinib is already generic. How much that is reduced the price? Ask Mark Cuban. We have to be thinking about the cost and it is a significant difference. That is a deciding factor oftentimes. Patients do not have the ability to pay copays of a $250,000 a year medications or whatever it is. Cost is a big issue.

 

Other things, when you look at the study design, many would argue, "Hey, I do not use dasatinib 100 mg. I use dasatinib 50 mg." I continue the drug for 5 years as opposed to 3 years to stop. I end up seeing just as good MR4 as MR4.5. It is not as easy as the study was overwhelmingly positive. I think you have to sit down with the patient. You have to talk to them about the pros and cons of each, and you have to have a shared discussion. Ultimately, maybe it is the insurance company that ends up deciding.

 

Dr Moore: Yeah, excellent point. I know we obviously talked a lot more biology types of things, but I remember referring in the beginning, financial toxicity certainly a really major thing that we need to think about, especially as patients are on continuous treatment for potentially years and years at a time.

 

Dr Fancher: I would weigh in just a logistical standpoint, if you were practicing at a community center where we have pathways and our pathway has not yet been updated to reflect some of this hot off the presses data. For a practitioner who is not as familiar with CML, who may go to our pathways for reference or for backup, and it is not there, it is not in the front of their minds yet. They do not want to be the one that tries the new drug, even with convincing data to your point, Anthony, again, old habits die hard. Again, pharmacists, maybe we need to be pushing a little heavier for updating our pathways in a more timely fashion or reminding practitioners there are outside alternatives to what is in the pathway.