Community Practice Grand Rounds: Practical Guidance for Optimal Multidisciplinary Management of Chronic Myeloid Leukemia3 Big Questions in CML treatment  

We have 3 big questions at CML. How do we differentiate patients that do or do not respond to a therapy, relapse over time, and what about discontinuation? What are the reasons behind this? Is it just bad luck or selection? Is it the immune system? Is it resistance and progression and the biology of the CML? I think these are the philosophical questions. We want to get the highest response rates, we want to avoid relapse, and we would love to get most of our patients or all of our patients to a cure.

[00:08:11]

Prognostic Scoring Systems for CP-CML  

How do we risk stratify patients with CML? This has not changed that much. If you look at a newly diagnosed CML patient, this is a complicated mathematical equation. I want to note that these are available online. You can see some links, down the bottom there for web links, and you can calculate them quite easily. But the Sokal, Hasford and the European long-term survival score really are not complicated. They take into account things like the patient's age, their spleen size, blasts, and their peripheral blood and platelet count, things that are readily clinically available. They really are easy to help predict what the likelihood of surviving CML with the most recent score, the ELTS, or the projection for response to therapy using Sokal, Hasford, and mind you, those were developed in an era before TKIs are available, but they are still relevant.

[00:08:56]

Value of Milestone Achievement in CP-CML  

That being said, we have come a little bit further along the way with regards to our milestones, and how do we really judge a CML patient, and response to therapy.

If you look at the BCR-ABL level, which is by PCR, which we just had this case question, we can really see that we are looking over different time points, 3 months, 6 months and 12 months. If we look at the descriptions of the responses, for a chemo patient, an early molecular response, that is at 3 or 6 months, the BCR-ABL level, which is the marker of disease, easily measured by PCR, we want to see it below 10%. That is really associated with improvements in progression-free survival and actually the likelihood of getting into a deep remission. Also relevant would be a BCR-ABL level less than 1% at 12 months. That is the equivalent of a cytogenetic complete remission, thinking historically. Had you just done bone marrow testing, you would see the cytogenetics are normal. That is also associated with superior survival.

Getting into the detail of deep molecular response, we know we do aim for a major molecular response, ideally at 12 months if possible, and that is associated with an increasing chance of achieving a deeper response and some improvement in progression-free survival. Lastly, deep molecular response, which is not necessarily BCR-ABL-negative. It is really just BCR-ABL levels that are low, below a 4 log reduction or even a 4.5 log reduction. That is not necessarily a treatment success failure milestone. It is more of an ability to facilitate treatment-free remission.

These milestones are measured over time, and you can see that there are different levels of caution where someone may be full green lights that they are sensitive, you continue. There may be milestones where you might want to ask about compliance, adherence, potentially do testing for resistance, or other questions. There may be categories where there is real caution that testing may be warranted, and even a switch may be warranted. If there is possible resistance or resistance, you should be thinking about changing or stopping your current therapy and moving on or you should. These are in the NCCN guidelines. It is a traffic light approach.

[00:10:56]

Approved BCR::ABL Targeted Therapy for CML in Adults  

Since 2001 we have had a steady stream of approvals in CML. Imatinib was the first TKI prototype approved initially after interferon and then for frontline therapy and doses, as you can see on the right, 400mg daily as a standard dose.

The next drug approved was the dasatinib, which was tested in the setting of resistance or intolerance to imatinib. It is now approved across different lines of therapy, and it is actually quite incorporated into advanced disease, including ALL with TKIs and Ph chromosome-positive lymphoid blast crisis.

Nilotinib was another second-generation TKI, which was also tested in a similar fashion. Not used in blast crisis, used in accelerated phase, and has different dosing depending on whether you have resistance or you are using in the newly diagnosed setting.

Bosutinib was the last of the second-generation TKIs approved across the line. Again, extensively studied. The dose you can see is also like nilotinib, slightly different, whether it is newly diagnosed or resistant intolerance that you are dealing with. There may be some tolerance issues with bosutinib that warrant dose escalation or dose escalation due to response as well.

Ponatinib and asciminib are in the next-generation class. Ponatinib has been available for a while. We call it a third-generation TKI. It was really developed as a novel agent that was able to combat the T315l-positive resistant mutation that we see in chronic phase CML and advanced phases of CML. It has gone through several iterations of studies, including dose optimization studies. We do start at 45 mg still across the board, with a plan to dose-reduce once patients respond. There are some modifications for certain patients, for example, with hepatic impairment. Again, much like dasatinib, if it is quite well incorporated into advanced CML, Ph-positive ALL, lymphoid blast phase particular, and even myeloid blast phase.

Asciminib is a newish drug. I think we will hopefully cover that well today. That is a STAMP inhibitor specifically targeting the myristoyl pocket, which is a slightly different area in the kinase that all the other TKIs are aiming at. Because it is a small molecule inhibitor that is quite specific and potent, it is active against T315L by mutation like ponatinib, but it also has a different potential mechanism of resistance distinct. It is able to overcome most cases of resistance or intolerance, and it has its own narrow band of resistance based on a different binding site. It has not been tested in an advanced phase to the point where it is been approved. But in chronic phase disease, it is actually licensed in the frontline and also for resistance and intolerance. Notice there is a differential dosing for patients with the T315l where they do get a much higher dose, albeit with similar safety.

This is the playing field, if you will. We have many drugs to choose from.

[00:13:39]

Deeper Responses to Second-Generation TKIs  

We are always looking to see how we can do better. Of course, the principal here was imatinib that was not interferon compared to imatinib. That was patients who got imatinib or patients who quickly switched over from interferon to imatinib, and their 10-year overall survival was quite good.

However, if you look at the graphs to the right and the on the bottom, in the first 1 moving on is nilotinib vs imatinib, and that is the major molecular response rate for frontline therapy with nilotinib vs imatinib. The next 1 would be dasatinib vs imatinib. You can see the advantage of dasatinib also with major molecular response. BFORE would be bosutinib. On top are some of the more summaries of the different response rates. What the second-generation drugs were able to do would be to engender deeper and faster responses and limit progression to advanced phase. Those are, of course, very important.

[00:14:33]

ASC4FIRST 96-Wk Update: Cumulative Incidence of MMR, MR^4 and MR^4.5  

The differences have been that we have not necessarily seen survival differences. What about asciminib? This is the newest drug, and this was the newest trial.

This was the ASC4FIRST trial. Patients newly diagnosed with chronic myeloid leukemia were randomized to either what a physician might have assigned as their best choice for therapy, whether it was imatinib, or a second-generation TKI or asciminib. You can see, looking at the going left to right again, major molecular response rates, asciminib also had an advantage. Now this is against all TKIs, imatinib, nilotinib, dasatinib and bosutinib.

Then if you look at the 2 figures to the right, the first would be the advantages of asciminib over imatinib, that is what is called the imatinib stratum. You can see it is even wider than the overall improvement. The difference between asciminib and the second-generation TKI is more modest. But it is evident, and this was a difficult trial to power for specific differences between asciminib and all of its competitors because it was a "physician's choice" trial. But quite impressive that asciminib can improve on all of the currently available frontline therapies. This is why it was licensed in the frontline. On the bottom are the improvements in molecular responses. You can see that those are also starting to accrue.

We really have quite a winner here with asciminib as a novel agent with a novel mechanism of action with advantages over all of our current frontline therapies.

[00:15:57]

Factors to Consider in CML Treatment Selection  

Okay. That is the treatment landscape. What about the selection, and how do we look?

Many different factors. We want optimal selection. We are going around the circle. What is our goal of therapy, and what are the patient's preferences regarding treatment-free remission survival. Well, of course they would love to be cured. Sometimes it changes depending on the age or the circumstances of the patient. Although I would say that treatment-free remission really should be a goal for all. The risk is something we calculate, and we should play into our decision-making. Ease of administration is related to the patient and their health issues and their situation, as are comorbidities. Certain comorbidities might move you away from a certain therapy because the risk of adverse effects or other.

Drug interactions are something we should have to be paying attention to and discuss, for example, proton pump inhibitors with dasatinib, food exclusion required for nilotinib for asciminib, not terribly difficult if it is a once-a-day drug, but more difficult for twice-a-day.

Then, of course, cost. We cannot expose patients to financial toxicity. A lot of discussion about that, especially in the United States that access and newer drugs, of course, being more at a premium, and older drugs now available by generic and including low-cost pharmacies such as Mark Cuban.

[00:17:06]

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

How do we individualize these therapies based on comorbidities? Here is a list of things that you might want to think about for patients with CML and how to think. Someone with pleural effusion, pulmonary arterial hypertension, those are the things we see with dasatinib. Maybe we avoid that. You may not know about those things upfront, but if you did, would want to take heed.

QT prolongation is an issue with nilotinib. Perhaps avoid that. To a smaller degree, hemorrhagic complications on dasatinib. I do not think that is a strong case, but it is possible.

Adherence. If you have a patient that you really think it would be a challenge to take a twice-a-day drug on an empty stomach, fasting on nilotinib can be a challenge. I just want to point out there is actually a new formulation of nilotinib available, which does not require fasting, called Danziten, which could be an option.

Then if you look at patient's comorbidities and their risk of biochemical and other complications, you can see there might be considerations there for patients with hepatic impairment, renal impairment, patients with a high risk for pancreatitis. And lastly, patients with vascular disease. We have heard and read a lot about that, and we may want to favor some of the so-called safer TKIs or at least be using with caution nilotinib and imatinib. I do not want to say you do not use them when the patient has vascular disease. You certainly may need them, for example, ponatinib is a very good drug. But you have to monitor for cardiovascular disease presence, manage it well, and make sure it is not exacerbated by treatment.

[00:18:28]

Let's Revisit Our Questions  

Let us revisit our questions.

[00:18:30]

Posttest 1: Which of the following would cause you to investigate potential therapy change for a patient who has been receiving imatinib 400 mg daily with no tolerability issues?  

Hopefully, we have learned a little bit already. Which of these milestones is a flag for us?

Speaker: The poll is open. Please vote. Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

Dr Mauro: There we go. Okay. I think more of you are starting to recognize that those transcript levels in the single digits at 3-6 months are actually okay. We are looking for less than 10%. But if we get up to 12 months, then you still have above 1%, the patient maybe not responding optimally. It may warrant a change in therapy. Well done all around, I guess, me and all of us together.

[00:19:38]

Here is the rationale. According to guidelines, greater than 1% of 12 months is possible resistance. We should ask about adherence, drug interactions, and they may be able to continue. But you should potentially think about a switch.

[00:19:50]

Patient Case  

Back to our case. Remember the 50-year-old man with comorbidities and high-risk CML?

[00:19:56]

Posttest 2: In your clinical practice, which of the following target therapies would you consider most appropriate for this patient?  

What do we think we should be treating him with? Go ahead and answer now.

Speaker: Poll is open.

Dr Mauro: Now, I did say that each of these drugs is approved in the frontline. This may be a little bit more of a challenge to move the needle, but.

Speaker: Five more seconds.

Dr Mauro: No sleeping on the job. These questions are coming fast and furious.

Speaker: All right. Thank you. We will close the poll and share the results.

Dr Mauro: Well, I think the same. We shared some data on how asciminib, which is a newer agent in this space, really does offer some advantages in response. What I did not share was tolerability data, which, if it is not on the deck, I can tell you that it is an improvement. But dasatinib and imatinib are still reasonable options. I think bosutinib could offer more risk of side effects and nilotinib may be more of a challenge for exacerbating underlying coronary disease, for example, in this patient.

[00:21:08]

Those are some of the points here. Asciminib might be preferred because he has high-risk disease and comorbidities, but we are trying to aim for a deep response without bringing side effects. The ASC4FIRST trial, which was recently published and has longer follow-up, showed that we might have a greater chance of major molecular response compared to all the other options. Well done.

Interactive Q&A Session  

[00:21:30]

Interactive Q&A session. I am going to ask my moderator to comment on this.

Speaker: One moment. We can move on. If anyone does have any comments, they can put them in the chat.

Dr Mauro: There you go. Okay. Perhaps I can have a chance to review that, but we are talking about choosing therapy in the frontline. The point may be, how do you choose your next-generation TKI in the frontline setting? When might you consider asciminib, or have you been able to consider asciminib? It is relatively new. Then lastly, what comorbidities do you consider? But we have talked about those.

Novel Approaches to Monitoring Patients on Frontline Therapy and Treatment-Free Remission  

[00:22:14]

Moving on, we will continue the didactic here. We have novel approaches to monitoring patients and thinking about treatment-free remission.

[00:22:25]

Pretest 3: Which of the following patient conditions meets criteria for considering TKI discontinuation and attempting TFR?  

Again, more questions. Which of the following conditions meets criteria for considering TKI discontinuation?

1. 2 years of therapy;
2. BCR-ABL less than 0.01 for 2 and a half years;
3. History of accelerated phase; or
4. No evidence of quantifiable BCR-ABL.

Speaker: Poll is open. Please vote.

Dr Mauro: Now, mind you, we have not gone over these yet. This is a pretest. Do not worry. We will cover this.

Speaker: Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

Dr Mauro: All right. I think we have a smart audience here if you look across these answers. We will go over the data in a bit. But I think B would be a correct answer. I will tell you that in a history of accelerated phase CML, not a patient, generally we would think about treatment-free remission. You might have heard me drop a comment that it is not that patients need to be negative or be stable. They just need to have certain circumstances. We will go over that more in a bit. Okay.

[00:23:50]

Case 2: Patient With CP-CML Who Achieved Stable Deep Molecular Remission and Is Interested in TFR  

This is a deep remission patient, talking about TFR.

[00:23:54]

STIM1 Trial in CP-CML: Imatinib OS Without Recurrence  

If you were not familiar with TFR, the very first trial started way back in the 2010s, really. This is the long-term follow-up. Actually, 2007, to be correct. That is more than 15 years ago now. This is the STIM1 trial, which looked at imatinib patients treated into deep remission and then selectively discontinued.

What is this curve showing you? The survival without recurrence. You can see that there is a quick drop-off within the first 6 months, but then there is a very stable course for about a little less than half of patients going out to a very long period of time. Treatment-free remission or stopping therapy is effective in a subset of patients. Once you determine that a patient has been successful, they can have a very stable course of therapy.

[00:24:41]

Select Trials of TKI Discontinuation at First Line  

This has been studied again since 2007, and we have had a number of trials, including the original trials we just showed, which was imatinib, robust though more than 100 or so patients. Then we started to explore patients who had exposure to second-generation TKI, exposure to dasatinib, nilotinib. We had the EUROSKI trial, which was the largest, which actually looked at patients who stopped at varying time points, maybe anywhere after 1 year of deep remission out to many, many years of deep remission, which helped us understand what is the optimal amount of time on treatment and in deep remission for which treatment-free remission can be successful.

If you look on the right of this busy table, you can see the TFR rate. It does vary a little bit, but it really does fall on or about 45-50%, especially as we get into the more recent trials. I feel dumb sometimes when I talk to patients, saying that it is about a 50-50 chance that a treatment-free remission will be successful. But ironically, with thousands of patients now, that is what we see.

[00:25:41]

Criteria and Considerations for TKI Discontinuation  

How do we consider treatment-free remission? These are the basic ground rules. That is in the colored figure on the right. This is in adult patients because pediatrics may be slightly different. Chronic phase CML, no history of progression because that may be a different biological entity, and there may be more risk. They need to have 3 years of treatment. They have to have evidence, of course, of BCR-ABL that you can measure. Then the last point is probably the most important, that they need to have a stable molecular response that is below 0.01% for 2 or more years on multiple tests. Basically, test it in a standard fashion.

Then on the left, what do we do? If patients meet these criteria, we can offer this option. It is not an expectation, but it is an option. Then they undergo more stringent testing. Monthly testing for the first 6 months, twice a month for the next 6 months, and then we continue to monitor them as if they were on treatment quarterly thereafter. Interestingly, that has not changed even for patients that are successful and into successful treatment-free remission for many years.

What are the criteria to restart? It is loss of MMR. The PCR studies show that if the BCR-ABL level is above 0.1, we resume rapidly. We then continue to monitor, and we want to see them regaining major molecular response. We monitor more frequently, and then we slip back to quarterly monitoring thereafter. Consider mutation testing if a patient has not regained molecular response. That is very infrequent, but it is just something to note.

[00:27:18]

Do Adverse Events Occur With TKI Withdrawal?  

Interestingly, you might think that stopping therapy would just be without adverse effect. But there is an interesting withdrawal syndrome that happens in about a quarter of patients, and they often have musculoskeletal symptoms, which is relatively predictable in timing and relatively limited. Interestingly, it can be treated with histamine blockade, and it usually disappears after a few weeks. But it can be something to pay attention to because it can be symptomatic.

Let's Revisit a Question  

[00:27:55]

Let us revisit the question.

[00:27:46]

Posttest 3: Which of the following patient conditions meets criteria for considering TKI discontinuation and attempting TFR?  

Which of these conditions meets the criteria for considering TKI discontinuation?

Speaker: The poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr Mauro: You guys are doing well. All right. I think we had 40% of patients noting that that was 1 of the criteria.

[00:28:36]

Two years is a little bit short, and no accelerated phase. Again, it is not that they need to be negative. Just to reiterate, those are the criteria, again, listed in the bullet rationale. Well done.

Interactive Q&A Session  

[00:28:50]

Again, the context of the interactive Q&A, this might be a little bit more for a live audience, but we are live on the web. But the thought here would be, if you want to enter any questions or comments into the chat about when and how you decide to pursue treatment-free mission. Some people may individualize it.

My advice would be guidelines are key, and probably the most important thing for patient consideration is to make sure a patient is not lost to follow-up, because this is an intervention, much like treatment. Treatment discontinuation is not a casual endeavor.

To Switch or Not to Switch: Optimal Strategies to Address Treatment Failure  

[00:29:24]

What about switching or not to switch? That is the question. What about treatment failure? Let us cover that now.

[00:29:30]

Patient Case  

Another case. Similarly aged person but now it is a woman who is a former smoker, also with coronary disease and a recent MI. That seems to be a common problem in this lecture. She is diagnosed with chronic phase CML and started on bosutinib. At 12 months our BCR-ABL level is 0.18%, but then at 18 months it has now risen to 3%. You have done your homework. No drug interactions, she is adherent, which is tough sometimes with bosutinib. You do mutation testing, and she has got a T315l mutation, which can happen.

[00:30:00]

Pretest 4: Which of the following is the most appropriate therapy for this patient?  

What is the most appropriate therapy for this patient?

Speaker: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr Mauro: Okay. Our lead answer is asciminib at the 200 mg twice-a-day dose. Our second choice, close call for asciminib lower dose and ponatinib 30 mg. We have a few folks choosing bosutinib and a few folks choosing ponatinib 45 mg. Let us get into this and see what we think.

Case 3: Patient With Resistance to Second-Generation TKI  

[00:30:55]

Resistance and Mutation Analysis  

Resistance and mutation testing. Not surprisingly, if you have a targeted therapy, we have through the span of TKI development, understood that point mutations can develop. When patients have treatment failure, a bone marrow study can tell you about clonal evolution chromosomes karyotype, which is important to highlight because that is a classic mechanism of defining disease evolution. It is not always about BCR-ABL mutation. That is a very important consideration.

However, BCR-ABL kinase domain mutation testing is recommended if a patient has treatment failure with imatinib or a second-gen TKI definitely in patients who progress. Of course, there is always a comment that you always want to assess treatment adherence and drug-drug interactions before you confirm resistance.

What kind of mutations are a problem? This list on the right just shows you the landscape. I will start from the bottom and say that there are no any mutations per se, at least point with single mutations that we know in which ponatinib would not be effective. That is not to say that certain mutational scenarios are potentially resistant to ponatinib or show lesser efficacy. Nilotinib has a fairly broad list, including T315l and some of the P-loop and A-loop mutations. Dasatinib looks similar, although it has some more specific mutations. Bosutinib looks similar to dasatinib in many ways.

Now, some of you might notice that there is a new group called the myristoyl pocket mutation group, P37465. But there are also some of the mutations that are in the ATP binding pocket. It might raise a question how is it that an asciminib because it is a newer drug, more potent, potentially more efficient. It has got its own mutational risk based on how it works. But why would it be resistant to mutations in other regions? It has to do with the way the drug binds. This is a kinase. This is a 3D living structure with activation status, open and closed configuration, and so on. It is a complicated story.

I do not want this graph just to instill concern that an asciminib is prone to resistance at a high rate or that ponatinib is the perfect drug, that that is not the answer. It is just that this is the prescription for lists of mutations that are to be looked for and sort of guide you.

[00:33:03]

Response, PFS With Second-Generation TKIs in Imatinib-Resistant CP-CML  

What about second-generation TKIs after imatinib? This is somewhat older data, but if you look at the bottom, I think the bottom 3 lines: major set of genetic response, complete set of genetic response and progression-free survival. They are pretty similar. Roughly 50-60% major set of genetic response after 2 years-plus, roughly 40-50% cytogenetic complete remission, and then roughly 80% progression-free survival. That was how well we did with second-gen TKIs.

[00:33:32]

Treatment of TKI Resistant CML  

How do we sequence? We have ponatinib as well, and we have asciminib now. We have jumped ahead to troubleshooting these cases. If you started with imatinib, you could consider that any of the second-generation agents and a STAMP inhibitor like asciminib would be reasonable. If you started with a second-generation inhibitor like dasatinib, bosutinib, or nilotinib as your frontline TKI you may consider another second-generation inhibitor, but you actually may need to move to another generation inhibitor like ponatinib. You can see that the approach for ponatinib is 45 mg. If you have a T315I, you could consider a lower dose if you do not. Then, once the patient responds, you move down to the lower dose of 15 mg.

What if you are starting with asciminib? Because I am touting that as an option. That is going to be an increasingly common scenario. It is not clear, but dasatinib seems to be the most commonly used and may be quite active.

What about third-line? Ponatinib is probably a drug that is occupying a lot of the third-line options, as is asciminib. The dosing scheme of a ponatinib is mentioned. Again, any alternate TKI including the STAMP inhibitor asciminib. If you are into your third-line of therapy or you have high-level resistance, remember that CML is a disease that is very well treated with hematopoietic stem cell transplant or allo grafting. If it was not discussed early, it probably should be at least assessed if a patient has a reasonable path with that. Do they have a donor that has been assessed, and so on. There are some other drugs that can be used that are fairly limited in their long-term efficacy, but they can control blood counts and temporarize the disease.

[00:35:12]

Phase II PACE Final Results: Response to Ponatinib in Patients With CML Resistant to >=1 TKI  

What about ponatinib? How did this drug fare? This was the PACE trial, which was in patients with multi-TKI resistant CML. How did they do with regards to cytogenetics and molecular response?

The curves on the bottom are probably a little bit easier to read. It breaks it out by the total population resistance or intolerance in patients with the TK15I. The major set of genetic response was quite durable as is major molecular response, so cytogenetics molecular response. The bar graph above, what are the differences in responses? Major complete psychogenic response on the left and then molecular response. Green is the T315I patients. You can see they actually do almost better than the general population. That is because they have a selective resistance, and ponatinib is quite effective against that. For these patients, ponatinib is highly effective. For the total population it is not much different, but it is slightly lower. But you can see very good rates of salvage for ponatinib.

[00:36:08]

The OPTIC Approach: Efficacy and Safety of Ponatinib  

That trial, however, revealed that there were significant amounts of vascular and arterial occlusive events. The OPTIC trial looked to optimize this drug and actually asked about dosing. You can see on the bottom right the scheme is of 45 mg reducing to 15 mg, 30 mg reducing to 15 mg, or just starting with 15. The treatment-emergent adverse events and dose modifications for arterial occlusive events they were better as you get to lower doses. However, if you look at the bar graph on the left, the BCR-ABL response rate, moving to the left of 45 mg starting dose was clearly better than 30 mg or starting with 15 mg at both 12 and 16 months. While we saw some reduction in adverse events and adverse events related to arterial occlusion, we did not see equivalence with response at lower doses, leaving us to say the 45 mg should be preserved as the primary dose.

[00:37:15]

Comparative Efficacy of Third-line TKI Therapy for Achieving CCyR in CML  

This is a complicated table, but it looks at the probability of cytogenetic response based on third-line therapy depending on whether you have had imatinib and dasatinib, and imatinib and nilotinib. You can see that the probabilities for ponatinib are much better either way, depending on what your permutation was. These were all the trials that looked at recycling the second-generation TKIs compared to ponatinib. Ponatinib generally does better than recycling a second-generation inhibitor. If you have had multiple lines of therapy, you have had imatinib and dasatinib, if you have had imatinib and nilotinib, ponatinib is more likely to bring on response, much like it did with the first iteration.

[00:37:53]

BCR::ABL1 Targeted Therapy Mechanisms of Action  

What about the STAMP inhibitor? Let us cover that. Again, the conventional TKIs bind the ATP-binding pocket, and the asciminib binds what is called a myristoyl pocket or corrects a defect that is created when this variable fuses in the myristoyl and the pocket is altered.

[00:38:09]

ASCEMBL: Asciminib vs Bosutinib for CP-ML Previously Treated With >= TKIs  

The first comparative trial after it went through Phase I and was shown to be highly effective and safe was a randomized trial vs bosutinib. This was again in multi-TKI resistant CML. I would say it is kind of similar to the PACE trial. Here patients were randomized to either bosutinib or asciminib. Now, they could not have had a T315I or a 299 mutation because you could not randomize them to bosutinib. This was really showing which would be a better third-line therapy.

[00:38:40]

ASCEMBL: Asciminib vs Bosutinib Responses  

This is a busy table, but if you look across the top, the major molecular response rate at a year, almost double asciminib vs bosutinib. The BCR:ABL level is less than 1%, more than double, and the cumulative major molecular response rates and the ability to maintain MMR rates were clearly better. Asciminib was roughly twice as effective as bosutinib. And actually, much better tolerated, leading to its approval in that setting.

[00:39:09]

Phase I Study of Asciminib in Previously Treated CML With T315l Mutation  

This is moving backwards a little bit. I did mention there was a phase I trial, but how did asciminib get approved in the setting of the T315I mutation? Actually, in the Phase I study, there was a fairly sizable cohort of patients, including those that had had ponatinib already, who received asciminib at this higher dose, which was formulated because of the potential complexity of the T315I mutation and how asciminib was binding. You can see that the response rates were quite good for cytogenetic response equivalent, which would be the 1% level BCR::ABL. Then molecular responses. Nearly half the patients achieving MMR were about a quarter achieving deep molecular emissions.

The adverse effects were similar to the lower doses of asciminib. This really showed us that asciminib is a proven strategy for this select form of resistance without really bringing greater toxicity.

Case 4: Patient With Intolerance to Imatinib  

[00:39:58]

What about intolerance? That is not common, but certainly something we also have to deal with.

[00:40:06]

Toxicity Spectrum of BCR::ABL1 Targeted Therapies  

Someone is on imatinib and they are having intolerance issues. Imatinib was on top here, fluid retention GI effects. Some of the things that can be quite a nuisance. What other side effects are common with the drugs as we go around the circle

Dasatinib, more things that we need to monitor for: pulmonary arterial, hypertension, pleural effusion, pericardial effusions.

Bosutinib, much more clinically evident: nausea, vomiting, diarrhea, fluid retention to a lesser degree. What about nilotinib? Many things that we also need to look out for: pancreatic enzyme elevation, metabolic syndrome, worsening blood sugars, elevated cholesterol, but also vascular disease, much like a ponatinib.

Ponatinib can clearly cause hypertension because it is a VEGF inhibitor, can cause vascular occlusion, it can also cause pancreatic enzyme elevation. Probably only 1 of the more complicated drugs to follow.

What about asciminib, the last on the bottom? Can cause some hypertension, like some of the other drugs, can cause pancreatic enzyme elevation, which you can see is fairly broad. Actually, really happens with most drugs. Then fatigue and nausea. Not a heavy burden of side effects for asciminib. Has a little bit of some of the other drugs in the classes, but nothing that is not too manageable.

[00:41:13]

Management of Treatment Intolerance in CML  

How do you manage intolerance? You also obviously think about switching to a drug that is better tolerated. You may even think about moving into the third-line options. It is a little tricky to think about ponatinib as a drug to switch to for intolerance because of some of the risks. The STAMP inhibitor asciminib really offers a nice alternative there. You may even think about a patient with multidrug intolerance. Sometimes patients cannot tolerate therapy. Although it sounds odd, they may actually need to move on to more definitive options. You select based on the patient's comorbidities. Mutation testing is still important even in intolerance because you may have mixture of intolerance and resistance. The general principle is we generally do not want to rotate second-generation TKIs if there was resistance and no guiding mutations. That is really more of a comment for resistance and intolerance, but it is here on this slide.

Let's Revisit a Case  

[00:41:06]

Let us revisit this case.

[00:42:08]

Patient Case  

Let us remember the gal we talked about, coronary disease, on bosutinib, former smoker. Reasonable response at 12 months, although a little bit off. Then, unfortunately, increasing in 18 months. Taking a drug, no issues with drug delivery, but with a TK15I mutation.

[00:42:26]

Posttest 4: Which of the following is the most appropriate therapy for this patient?  

What do we think is the most appropriate therapy for this patient?

Speaker: The poll is open. Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

Dr Mauro: How do we do it? Well, again, great learners. We shared a lot of data on the differences and the choices we have. We are seeing a lot of cases with patients with comorbidities.

[00:43:10]

Asciminib 200 mg twice a day would probably be a good choice for this patient. There is a T315I mutation which responds to this drug at that dose. It would probably be preferred over a ponatinib, which is 2 of the choices here, due to the strong cardiac history, coronary disease, recent MI. Again, just to highlight to mention the difference in dose. That is why the 80 mg is too low, 200 mg is just right. Remember, bosutinib is not active against T315I even at full dose, and ponatinib just poses too much risk here.

[00:43:43]

Summary  

To summarize, there are differences between the TKIs. You can combine the principles of the drugs and what side effects they might bring, what their efficacy profile looks like, how they are administered, and look at disease-specific and patient-specific factors and individualized treatment.

It is not easy to treat CML per se, but there are many choices, and the response can be quite easy to achieve high rates of success. But you have to work at it. Recognizing and interpreting treatment milestones is really of the utmost importance. We went over the diagnosis to a lesser degree, more the monitoring. Obviously, PCR is the driving force of monitoring and looking at molecular testing at key milestones and essentially not waiting for the patient to fail, but recognizing that the response is not happening fast enough and adjusting therapy.

This is definitely a very specific scenario where engaging the patient is necessary. Physicians and patients, practitioners and patients, nurses and patients, and us with their healthcare team, family, friends, loved ones. Adherence is key. We did not cover some of the data, but adherence is probably one of them. Or patients inadvertently lowering their dose or stopping for reasons that they did not discuss with us, can be 1 of the key reasons for patients to lose their response or to not be able to achieve a deep response or to, for example, fall out of deep remission.

We talked a lot about TKI discontinuation. Safe and with appropriate criteria consenting, meaning they understand the risks and benefits. Again, please do not have these patients lost to follow-up. It can be successfully accomplished in a fraction of patients, and there is about a 50% success rate. In the end, we get about a third of patients in the best of circumstances to a treatment-free remission with our newer therapies, but I think it certainly should be a goal of therapy.

[00:45:40]

Poll 3: Do you plan to make any changes in your clinical practice based on what you learned in today's program?  

Some poll questions to maybe close this out. Do you plan to change your clinical practice based on what you learned today? How did I do?

Speaker: Poll is open. Five more seconds.

Dr Mauro: No pressure, by the way.

Speaker: All right. Thank you. We will close the poll and share the results.

Dr Mauro: Oh, that is very kind. Thank you. Uncertain is fine, too. No might mean that you know all this already, and you are doing well with your CML treatment. I know there were a lot of questions, a lot of interaction. I really appreciate your engagement. But we really wanted to see some of the key questions. There are a lot of threads here going through a newly diagnosed patient and monitoring a resistant patient, and a tolerant patient and treatment cessation. Well done.

Sorry. Again, no QR code. I will let the moderator drive this one.

Speaker: Thank you. Yes. As you can see, but we do have a text box where you can type in a key change that you plan to make in your clinical practice based on this education. Dr Mauro, you can go ahead and move forward, and we will leave this open for a few seconds so people can enter their responses.

[00:47:19]

Interactive Q&A Session  

Dr Mauro: Okay. Maybe you guys can let me know if we have any questions or comments in the chat that I can answer. I got us to the finish line a little bit early, which I was fearful we did not want to run you over. I know everyone's got a busy day ahead. But I am hoping you were able to learn something this morning, or this afternoon, or the evening, wherever you are, and integrate these into your practice.

Speaker: Thank you, Dr Mauro. We are now taking any questions that you may have for Dr Mauro. Dr Mauro, I do see there are a few that have come into the Q&A, if you would like to start looking at those. Please submit those. Any others that you may have in the Q&A section. While you do so, I wanted to point out there are a few links in the chat panel. Also, Dr Mauro, if you could advance your slides, there should be a couple of QR codes.

[00:48:11]

Thank You for Attending Our Program!  

Okay. There are not. Okay. There are links in the chat panel. One will lead to the downloadable slide deck from today's presentation, which several of you have asked about, and the other will be to the program evaluation link that you will need to complete in order to claim your CME credit. You will need to log in to or create a CCO account, and you will need to claim your credit within 30 days, as credit for today's program will expire after this 30-day time frame. Dr Mauro, are you able to see those questions that have come in?

Dr Mauro: Yes.

Speaker: I can read those to you.

Dr Mauro: And I will answer them live. One was a very broad but accurate question. Does cost play a factor? Dasatinib is generic. I briefly touched on that, and I think it clearly does. The most important thing is that a patient has easy access and continual access to a therapy that is effective for them. The good news is, is that imatinib is still a very good drug and effective in many patients. It is not perfect. It is available by generic form and at a low cost, and it is actually widely available globally.

Dasatinib is also available as a generic. That is a somewhat better drug with a fairly flexible dosing schedule. That is a huge boon to patients. I would not discourage patients from using lower-cost generic drugs. However, in the discussion, if it is feasible and accessible, the newer drugs can offer advantages. I think we have to have a balancing act. I think our healthcare system in the US is complex. At a global level, that may be different. Everyone has to think about their own circumstances. But the great story here is that the therapies we have moved through different generations, you can see that we have shed none of them. They all remain as good options. That is a great question. I would encourage people to try to look for low-cost options or generic options. But the goal, again, is a treatment is only successful if a patient has access to it and can take it and can take it over the long term.

The second question was about a woman who had not had as much monitoring, but 5 years of imatinib with low BCR::ABL levels and had to proceed maybe about treatment-free remission. There I would just go with the guidelines. If someone has met criteria, it is reasonable to think about a treatment-free remission. Again, most importantly, that they need to be able to be followed. It sounds like this case it might not be all the data. The 2 years of deep molecular response, measured over several time points. It is a little tricky. If someone's tolerating imatinib, there is really no harm in taking treatment longer. But if it is a 32-year old woman, maybe she wants to have a child, maybe there are other agendas. That is a great question and brings out a lot of points.

Then the last question I see on the chat right now, are we seeing long-term effects from imatinib in patients who have been on therapy for many, many years? They are noting some renal issues, some kidney problems. That actually is something that has been looked into. I will tell you that there is a very interesting story there, that the monitoring of patients with long-term CML therapy and some change in creatinine clearance and glomerular filtration rates may be actually an artifact of the way the test is measured and the co-administration of imatinib. We do see some improvement when patients ultimately stop, and we do not see progressive renal decline.

There is a little bit of a story with bosutinib and renal dysfunction as well. But for the same reason, we do not think it is actually an intrinsic renal damage. It may be an artifact of the way that it is being monitored and the presence of these TKIs. However, that opens up a bigger question about long-term effects. I think we need to study more patients' long-term treatment outcomes as we get more patients on treatment for very long periods of time and more patients entering what we call treatment-free remission attempts or success, really.

Those are some great questions.

Speaker: Okay. I do see one that came into the chat panel. Dr Mauro, how are you managing imatinib-induced generalized edema and/or periorbital edema? Thanks for a great talk.

Dr Mauro: Oh, thank you. Edema, there is some easy advice for the patient. Salt limitation is one, adequate treatment of blood pressure and other comorbidities. Imatinib can probably be through platelet-derived growth factor receptor, some pretty significant periorbital edema, which is really cosmetic in nature. It does not really affect vision, but it can be quite burdensome for patients. We actually delve into the sort of cosmetic advice here. Preparation H, cold compresses, cucumbers. You name it, I have heard it. Medically though, let me just answer that, diuretics can be helpful, but they are not as effective as you would like. They do not necessarily help with periorbital edema as much as maybe generalized edema, but they can be administered, I think, low-dose like thiazide diuretics, for example, things with not a lot of side effects are fine. But tricky.