A Master Class in CP-CML: New Agents, Treatment Goals, and Clinical Challenges

 

This is now a timeline that I imagine most people are aware of. I think it just points to 40 years of progress since we have really understood the molecular basis of chronic myeloid leukemia with the discovery of the BCR::ABL fusion back in the mid-1980s. Maybe that is the reason for the 80s music. Then imatinib approved in 2001 as really the first tyrosine kinase inhibitor approved for any malignancy and a real eye-opener, followed by dasatinib approved initially and nilotinib for second-line therapy. Then those 2 were approved in 2010 for newly diagnosed patients.

 

Bosutinib in 2012 for again second-line and beyond. Asciminib, 2021 in third-line and beyond. And asciminib getting the indication for any line of therapy in 2024.

 

[00:09:45]

 

The Impact of TKIs on CP-CML

 

You all, I am sure, are aware of the dramatic impact that TKIs have had on outcomes in CML. You can see on the left side here, the accelerated phase curves on the top. If you look at red, that is from basically in the TKI era, you can see they have been improved over the blue curve. However, the blast phase outcomes have not really substantially changed unfortunately, despite very good TKIs.

 

In the chronic phase, things are doing much better. You can see, if you look in the middle panel, 95% survival after a decade. If you look historically where that was, it is really remarkable success of what these therapies have done. On the right, it is just trying to show that the life expectancy now, of course, of patients with CML we expect to be very close to that of the general population.

 

[00:10:47]

 

Selecting Frontline Therapy for CP-CML: Overview

 

We have now a lot of information that CML, in the absence of therapy, progresses generally from an indolent phase to a more aggressive life-threatening phase, usually within about 4-6 years median time. The fact that BCR::ABL is what drives CML is, of course, led to the development of these 5 active frontline therapies that we have right now. That has dramatically improved survival.

 

Now, again, we have this luxury of choice, which is great for patients. It is great for physicians. At the same time, it is really important to really think about how we can really further improve outcomes by getting the right therapy to the appropriate patient.

 

[00:11:32]

 

Studies of Frontline BCR-ABL TKIs in CML

 

I am going to talk briefly about some studies of frontline BCR::ABL TKIs, so we can all be on the same page here.

 

[00:11:42]

 

Imatinib in Newly Diagnosed CP-CML: Excellent Estimated OS Rate at 10 Yr

 

These data are not new. This is imatinib in newly diagnosed patients. This was the study that compared it head-to-head with the previous medical standard of care, which was interferon and cytarabine.

 

Now, although the survival curves here are not that different, keep in mind that the interferon patients were able to cross over to imatinib. The important thing here is that with 10 years of follow up, the survival rate is as high as it is in the imatinib era.

 

[00:12:11]

 

DASISION 5-Yr Update: MMR and MR Outcomes With Dasatinib vs Imatinib in Newly Diagnosed CP-CML

 

The second-generation drug, dasatinib, in the newly diagnosed patient population was compared directly with imatinib and shown to achieve deeper or higher proportion of major molecular response, as you can see here, so by 1 year 46% vs 28%. And also deep molecular response, which in my view is actually more clinically meaningful than a major molecular response because this is something that is actionable. This is something that leads us to actually be able to stop therapy.

 

You can see on the right that the second-generation drug makes that a realistic possibility for a higher proportion of patients.

 

[00:12:52]

 

ENESTnd 10-Yr Update: Cumulative Incidence of MMR in CP-CML With Nilotinib vs Imatinib

 

Similarly, for nilotinib, there were 2 different doses that were assessed, 300 twice-daily and 400 twice-daily, and compared with imatinib, again in newly diagnosed patients. Similarly, the major molecular response rate was superior with nilotinib either dose, as we know, 300 twice a day is the approved dose in newly diagnosed patients.

 

[00:13:15]

 

BFORE 5-Yr Update: MMR and MR Outcomes With Bosutinib vs Imatinib in Newly Diagnosed CP-CML

 

With bosutinib, again, the ability to achieve a higher rate of major molecular response and deep molecular response is shown again, as was the case for both dasatinib and nilotinib. You can see the magnitude of the difference here in this particular study.

 

Of course, bosutinib has had a little bit less uptake, because we had the other 2 drugs available for quite some time. It is a little bit hard to know entirely the extent to which bosutinib is equivalent. There have been studies demonstrating equivalence between dasatinib and nilotinib in newly diagnosed patients.

 

[00:13:57]

 

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

 

Then more recently, of course, is asciminib, which, as you know, has a slightly different mechanism of action than the other drugs. The other drugs are ATP competitive. Asciminib, in contrast, acts through targeting an allosteric pocket, and as a result of this, does achieve greater selectivity against ABL kinase, and possibly that may be responsible for improved tolerability.

 

You can see here the cumulative incidence of major molecular response on the left, a 4-log reduction in the middle and a 4.5-log reduction of asciminib. This is all major molecular response, I should say. On the left is the entire group, which is 200 patients roughly randomized to receive asciminib vs 200 for all the investigator selected TKIs, half of whom got imatinib, which we know is less effective.

 

It is perhaps not surprising that the blue curve on the left is a little bit less than on the right. You can see that more dramatically in the middle when you break out just the asciminib stratum vs the imatinib group.

 

On the right, you can see, if you compare it with the second-generation drugs, it is not so dramatic. There is maybe a trend. It does not meet statistical significance. This study was not powered to detect that.

 

[00:15:30]

 

ASC4FIRST: 96-Wk Update: Safety and Tolerability

 

In terms of tolerability, this drug does seem to be very well tolerated. That was borne out in this study. You can see the incidence of grade 3 or greater toxicities was less with asciminib than imatinib and the second-gen drugs. This translated to less treatment discontinuation and less need to interrupt therapy.

 

However, it is important to note that follow up is relatively short. We learned things about long-term toxicities of the other drugs, sometimes well after approval, including cardiovascular events. So this is being looked at very carefully. So far the data do not seem to show any sign. But of course it is relatively early.

 

There are also some rather unique toxicities of asciminib that we need to be aware of. Maybe not unique, but rather selective toxicity, such as pancreatitis and increases in blood pressure in a proportion of patients.

 

[00:16:39]

 

Deeper Responses to Second-Generation TKIs and Asciminib

 

If we look at deeper responses to second-gen drugs vs if we just look across all these studies, and we look at what I am calling here the complete cytogenetic response rate. This is not true complete cytogenetic response by marrow metaphase, but it is rather a PCR level of 1% or less, which we think of as being more or less equivalent to a complete cytogenetic response across all the groups.

 

I mean, these data look remarkably similar, right? On the left, you can see newer non-imatinib drug numbers between 77% and 84% vs 65% to 70% with imatinib. The major molecular response rate varies, as you can see here. As I said, to me the value of the 1% level on the left is clear that that improves overall survival. That is associated with improved overall survival. Then of course the deep molecular response. I view those 2 as being the most critical clinically significant.

 

But if we look at major molecular response, you can see again differences there. There is less transformation events as well you can see with the newer drugs compared with imatinib. Overall, the numbers are low, however, in all groups. Importantly, none of these newer therapies has thus far shown any improvement in overall survival compared with imatinib. I think a major reason for that is that we can identify patients that are not responding well to imatinib. Then in a timely manner, get them to a more effective agent. Dr Radich and we will talk more about that.

 

[00:18:23]

 

Approved BCR::ABL Targeted Therapies for CML in Adults

 

A very wordy slide here, but just a summary of all 6 approved TKIs. Ponatinib is listed here but is not approved for newly diagnosed patients. Not all of them are approved for accelerated or blast phase, as you see there. The dose may vary depending upon the phase of disease. For instance, imatinib 400 mg in a chronic phase vs 600 in an advanced phase patient. That is the case for many of the drugs as you see here.

 

It is also important to note that we are learning more. It is difficult to know what the optimal dose of any TKI is. Of course, these things always come to market relatively quickly, and the information that goes into choosing the dose that is tested in phase II and phase III studies is based on relatively limited data. We sometimes learn in retrospect that maybe the dose is actually higher than it needs to be.

 

It is important to keep in mind that, in many cases, especially with the more potent drugs, the second-generation drugs, and also asciminib, it is possible to treat with lower doses and certainly to reduce the dose, as I think Dr Smith is probably going to talk about in patients that are having tolerability issues.

 

[00:19:45]

 

Important Considerations for Selecting First-line TKI Therapy

 

Factors to Consider in CML Treatment Selection

 

Now talking about specific factors that we weigh. There are both patient-specific factors and disease-specific factors that factor into this. One of the important things is listed at the top here, that is, what is the goal of the patient. Are patients really eager to have a deep response so that they can try to stop therapy?

 

Of course, we want everybody, at a minim, to maximize the likelihood that they are going to live from a CML perspective and not suffer complications of their disease. But some patients are really hell bent on wanting to get off therapy. Those patients, it makes sense to be a little bit more aggressive, especially if they are younger, especially if they are thinking about childbearing and things like that.

 

Other patients are not so focused on that. There is also other patient-specific things like ease of administration. Some of the drugs are once-daily with or without food, others are twice-daily fasting. So if you have a patient that you are maybe a little bit worried about their ability to adhere to a twice-daily fasting schedule, that is important to take into account, as are comorbidities.

 

The risk score is really important, which we will talk about in a moment, because we know that especially if patients are at intermediate or high-risk chronic phase CML, they have a higher likelihood of responding better to second-generation drugs compared with imatinib.

 

Cost is something else that we are starting to pay more and more attention to. There are, as I mentioned, 5 approved frontline therapies, and now 4 of them are available generic. There is cost to society, but there is also importantly cost to the patient.

 

These are things that I think we are starting to pay a little bit more attention to as we are seeing some of these differences emerge.

 

[00:21:40]

 

Value of Milestone Achievement in CP-CML

 

In terms of treatment milestones, of course, we follow the disease by quantitative PCR. This looks at the p210 transcript and basically looking at various levels of response listed across the top. You can see, the response levels that are green are considered optimal at that specific time.

 

For instance, at 3 months we want to be ideally at 10% or lower. Similarly, at 12 months, we want to be at 1% or lower. These are again the milestones that if these are not being achieved, then especially if a patient is on imatinib, we want to try to maybe consider switching them to an alternate, more potent agent.

 

Now the major molecular response, I would like to highlight at the 12-month period, a level of 1%, in my opinion, that is adequate. Obviously, if a patient is really motivated to achieve a deep molecular response to try to stop therapy, then ideally a major molecular response. But in terms of a long-term prognosis, anywhere less than 1% puts them in the best overall prognostic category from a long-term survival perspective.

 

[00:23:09]

 

Toxicity Spectrum of BCR::ABL1 Targeted Therapies

 

There are also toxicity spectrum differences between the agents. There can be interplay of this with the comorbidities. They can all cause myelosuppression, myalgias, fatigue, etc. and brain fog. There are some that are more common with 1 drug or another. Those are listed. I am not going to go through them all, but I think these are all important things, because patients may have comorbidities that maybe put them at higher risk of not being able to tolerate some of these particular things. That can certainly impact the choice of treatment.

 

[00:23:51]

 

Frontline Treatment of CP-CML: Risk Stratification

 

As I alluded to earlier, the Sokal score, or Hasford now, the ELTS really are different ways of binning chronic phase patients into low, intermediate or high-risk groups. What is really critical to keep in mind is it is important to do a clinical assessment of spleen size prior to starting therapy, because that goes into all of these scores. Again, this is on clinical exam. This is not like ultrasonography. It is actually how many centimeters below the left costal margin can you actually palpate the spleen.

 

Each of these formulas are rather complicated, but they take into account the variables listed here the age, the spleen size, the CBC. Basically, we have learned that patients who have high-risk disease have shorter overall survival. The major molecular response rates are better in intermediate and high-risk, as I mentioned earlier, with the second-generation drugs or asciminib compared with imatinib.

 

These are important things to try to keep in mind. There are other things that are evolving, other biological features that we are learning about that may further impact this. Up until now, it is mostly just been clinical. Now we are getting to where looking deeper, looking beyond just BCR::ABL can help assess risk as well. I will get to that in just a moment further.

 

[00:25:34]

 

Prognostic Scoring Systems for CP-CML

 

These are those prognostic scoring groups. As I mentioned, they each bin patients into low intermediate or high-risk. There are 4 of these. I personally generally use the ELTS because that 1 seems to be the most predictive in the TKI era. Whereas some of these others were developed prior in the interferon era.

 

[00:26:00]

 

Individualizing Targeted Therapy in CML Patients With Specific History or Comorbidities

 

Other things, as I alluded to earlier, in terms of comorbidities, there are some specific cases where we absolutely want to avoid specific agents, and those are listed here. This is not an exhaustive list. But just keep in mind there is no perfect drug, absolutely. So this gives us an opportunity, again, to try to optimize patient care by getting the most appropriate drug to each patient.

 

[00:26:30]

 

ELTS RISK Score Can Help Stratify Optimal Treatment

 

This is the ELTS score. As I mentioned, it will bin patients into 3 different groups. Low risk is about maybe just close to two thirds of patients, a half to two thirds. Intermediate risk are about a quarter and then high-risk about 15%. You can access this online. It is a tool. I encourage you to use it, because as I mentioned, if it is a low-risk patient, as we will talk about in a moment, generally speaking, you feel a little bit better that imatinib may be adequate, not that it should be a preferred choice, but that it may be adequate much more so than if it is an intermediate or high-risk patient.

 

[00:27:15]

 

ELTS RISK Score Can Help Stratify Optimal Treatment

 

This is showing you here the predictive value of the ELTS score. You can see in red the low-risk patients are doing better. The good news is people on the whole, they are doing well, but certainly there are differences. That speaks to the importance of using this tool to risk stratify patients.

 

[00:27:41]

 

Common Mutations in CP-CML

 

Work has been done by many groups but largely by the group in Australia have found mutations in genes outside of BCR::ABL. These are genes that are on the radar because they are found to be mutated in other myeloid malignancies.

 

You can see the list of them there on the left. Many of these, I am sure, are familiar to you. But until we really knew where to look, we did not really have much of a roadmap. But about a quarter of patients will have a mutation in 1 of these myeloid malignancy associated genes. It seems like the main 1 to be concerned about is ASXL1. This is probably present in about 10% to 15% of chronic phase patients at diagnosis.

 

[00:28:46]

 

Impact of ASXL1 Mutations at Diagnosis on Survival Outcomes in Imatinib-Treated Patients With CML

 

You see on the right, it has been associated with a lower initial response rate. But I think more importantly, these patients seem to be at higher risk of developing kinase domain mutations later. That is something to keep in mind. It may be worth also starting to think about, in such a patient group, do we want to choose a drug that is relatively invulnerable, let us say, or unsusceptible to kinase domain mutations.

 

None of the frontline therapies are completely. But it does make us start to think that if kinase domain mutations are more likely to arise, maybe these patients would be better served with agents that have the fewest number of vulnerabilities.

 

[00:29:25]

 

Frontline Treatment of CP-CML: A Proposed Algorithm

 

This is a frontline treatment algorithm that Ariel Leyte-Vidal and I published. This is an e-pub in Blood, that basically is rather instructive. It is certainly not something that is written in stone. Certainly if you have a patient who is older, significant comorbidities or a reduced life expectancy for any reason, imatinib is basically fine. Whereas, if they are otherwise healthy and if they have low ELTS score and a strong desire to achieve a deep molecular response, then I think a second-generation TKI or asciminib is appropriate. If they do not, then imatinib is certainly acceptable, if they are low risk.

 

If they are high-risk, then I think they should be treated with a second-generation drug or asciminib.

 

One other thing to mention, that I do not have incorporated in this slide, is we have also learned more recently that there are some BCR::ABL isoforms. The vast majority of patients will have BCR::ABL fusion that fuses BCR to ABL exon 2. That is maybe 97%, 98% of patients. About 1% or less of patients will have a fusion with ABL exon 3. Those are not typically detected by quantitative PCR. They are sensitive to the ATP competitive drugs, but Ariel Leyte-Vidal in my lab and Inga Leske in Oliver Hantschel’s lab published that these are inherently resistant to asciminib. That is something to be aware of as a potential vulnerability for asciminib.

 

[00:31:24]

 

ASC4START: Asciminib vs Nilotinib in Newly Diagnosed Ph+ CP-CML

 

One last study I want to just talk about briefly. I mentioned that the ASC4 first study was not really powered to look for differences between asciminib and second-generation drugs. This is a study that was done that was powered to look for differences. In this study, newly diagnosed patients were randomized. You can see the numbers close to 300 in each arm to receive either asciminib or nilotinib.

 

There were 2 endpoints. The primary endpoint was the time to discontinuation from an adverse event. But of course it was also of interest to see if asciminib is actually better from an efficacy perspective than nilotinib, because as I said in the ASC4 first study, there is a trend, does not meet statistical significance, but certainly makes one wonder.

 

[00:32:12]

 

ASC4START: TTDAE With Asciminib vs Nilotinib

 

In terms of the primary endpoint, asciminib does seem to be better tolerated than nilotinib. You can see the discontinuation rate in red for asciminib. The cumulative discontinuation rate is lower than it is for nilotinib in blue. It definitely does seem to be better tolerated than nilotinib in this large study.

 

[00:32:37]

 

ASC4START: Similar MMR and DMR at Wk 48

 

In terms of efficacy, if you look here, if you focus at the bottom, if you look at MMR and MR4.5, on the left, you are looking at 12 weeks and in the middle at 24 weeks. In both those instances, it looks like asciminib is getting more patients to that response faster. If you look at major molecular response at 48 weeks or just about a year, you can see that they are really pretty similar. At this point, it is still debatable as to whether or not asciminib is more efficacious, maybe earlier responses in this study, but it certainly with respect to MMR, it does not look like at 48 weeks there is any superiority to nilotinib.

 

[00:33:27]

 

Tool Summarizing Factors for Planning a TFR

 

In terms of planning for treatment-free remission, a number of studies have looked at factors that can be more predictive of success. You can see listed here. One of them is gender. Certainly patients with low-risk disease at the beginning are more likely to be successful. That is not a surprise.

 

In terms of transcript level, most patients, as I said, will have an ABL exon 2 fusion. But those can either be with 13 exons of BCR::ABL, E13 or 14 exons, and it does seem that the 14 exon isoform is associated with a higher rate of treatment-free remission. Then there are other factors listed below. During treatment, not surprisingly, the more rapidly patients respond in general initially to TKI therapy, it seems to be a predictor for success, as does duration of treatment and duration of time in a deep molecular response.

 

Although, we greenlight people for discontinuation after 3 years of treatment and 2 years in a deep molecular response, it does seem that longer time on treatment and longer time in deep molecular response increases the likelihood of successfully stopping.

 

[00:34:42]

 

Treatment-Free Remission: Cure?

 

Now I am starting to think that a lot of these patients are cured. At what point do we say that? It has been 10, 15 years. This was work that was initially pioneered by the French, Francois Mahon and others.

 

If we look on the right, what we see is about 50% of patients with our current therapies do not get to that deep molecular response, so they are never eligible to try stopping treatment. On the left side of the pie, you see those that are able to try stopping. In blue are those that are successful the first time, so about half of them. Then of the rest that are unsuccessful the first time, about a third may be successful on a second time around. About two thirds of patients, unfortunately, at this time are looking at indefinite therapy.

 

[00:35:31]

 

TFR After Second TKI

 

This just speaks to the fact that I alluded to that it is possible to successfully stop treatment after a first failed attempt. On the right is something important, and that has to do with what the success rate is depending upon how long the first attempt went on.

 

If the first attempt was 6 months or longer before the patient had to resume therapy, they had a much higher chance of being successful down the road than if it was a less than 6 months.

 

[00:36:03]

 

Risks Associated With TFR

 

There are some risks that patients need to be informed. Some patients do not recapture the level of response. That is pretty unusual. There is something called TKI withdrawal syndrome, which is musculoskeletal pain that arises anew upon stopping treatment. Then there are some rare cases. We do not really know the denominator because this has happened largely after this has gone into real world experience. But there have been some rare cases of down the road blast phase transformation, primarily lymphoid. We cannot say there is absolutely zero risk with discontinuation. We just need to inform patients about this.

 

[00:36:41]

 

Possible Criteria for Selection of TFR as a Management Option in Consenting CP-CML Patients

 

In the interest of time, I think I have spoken about much of this before. I do not think I need to rehash this.

 

[00:36:51]

 

Selecting Frontline Therapy for CP-CML

 

But rather to summarize by saying that, hopefully, you can see that they are both patient and disease specific factors that help us individualize choice of therapy. The available data certainly suggests that the second-generation drugs and asciminib are superior in terms of achieving deeper molecular responses compared with imatinib and therefore facilitating treatment-free remission attempts in a higher proportion of patients.

 

They do not to-date achieve any superior overall survival. Again, that may be largely because we can switch patients that are not responding well to imatinib in a timely manner and get them on more effective therapy.

 

Imatinib is associated with the lowest risk of toxicities that are both serious and irreversible. However, it probably is also associated with the highest risk of bothersome day to day toxicities. Again, no perfect drug. As I mentioned earlier, I think since we have 4 of these generic and taking into account cost to society, cost to the patient is something I think we are going to be paying more attention to.

 

[00:38:00]

 

Available Resources From CCO

 

Here are some resources that are available to you. I encourage you to scan the QR code listed here. You can have access to more guidance on monitoring response to inhibitors.

 

[00:38:18]

 

Abstracts of Interest at ASH 2025

 

Here are some abstracts of interest at this meeting related to what I have discussed here. I encourage you to attend these. I will also just give a shout out to Ariel Leyte-Vidal from my group, who has got a poster on mechanisms of resistance to asciminib on Saturday evening.

 

[00:38:40]

 

Putting it All Together: Expert’s Approach and Takeaways on Selecting Frontline TKIs for CP-CML

 

Basically, when you are considering things to think about from this talk, or when do you consider second-generation drug vs imatinib, what factors are most important in your choice of frontline TKI? And if TFR is the goal, what is the preferred option?

 

[00:39:14]

 

          Posttest 1

 

Le us briefly revisit our questions. See if anyone’s confidence has improved since we started this so far. Okay. Looks like it largely.

 

[00:39:50]

 

          Posttest 2

 

Here is question 2. Which of the following characteristics can potentially impact efficacy and long-term safety?

 

1. Fewer complications with diabetes in patients receiving nilotinib;
2. Improved tolerability, and so on.

 

I think most people got this right the first time and hopefully that would not have changed. We hope it is a learning activity and not going in the opposite direction.

 

Okay. More people got the correct answer there, which I am glad to see that.

 

[00:40:53]

 

Q&A

 

With that, I will open up for like a couple questions from the audience or is there anything online? Doug has a question.

 

Dr Douglas Smith (Sidney Kimmel Comprehensive Cancer Center): Thanks. One of the questions, and we could talk about this forever. But just briefly, knowing the overall survival is not difference between first and second and third generations up front. Is there any reason not to just start people on imatinib?

 

Dr Shah: That is a great question. Part of my hesitancy to start people on imatinib vs 1 of the second-gen or asciminib is that, in general, the day to day tolerability seems to be less. Again, if anything you are looking at a higher likelihood of indefinite therapy. At the same time, I would never say it is malpractice to start somebody on imatinib, absolutely. I would just say my personal preference in general would be a second-generation drug or asciminib.

 

Dr Smith: Just 1 other question regarding treatment-free remissions. If someone fails their first attempt at treatment-free, and we will go ahead and give them 8 or 10 months of treatment-free before they fail, would you switch them to a different TKI when they go back on therapy?

 

Dr Shah: Yes. The only reason I would probably switch TKIs in somebody who failed the TFR attempt would be if they had tolerability issues for the most part because, if they are tolerating that therapy, well, I cannot think of a compelling reason. Obviously, we would love to hope. We would love to think that something could be more effective than 1 of these drugs.

 

I could say maybe if it was a failure on imatinib, then maybe you could construct an argument that a second-gen or asciminib may be more likely to push the disease even deeper and enable a second, but that is all speculative.

 

I want to hand it off now to Doug Smith. Thanks.

 

[00:42:59]

 

Grappling With First-line Treatment Intolerance in CP-CML: What Are the Next Best Options for Patients?

 

Dr Smith: Just so folks know, we really encourage the online questions. Please feel free to throw them out there. There is a couple that people brought into play with resistance and things. We are going to save that until after Jerry's done. We will have a chance to ask him a question about that.

 

[00:43:23]

 

          Patient Case Continued: 52-Yr-Old Experiencing AEs on Imatinib

 

I am here to talk a little bit about the struggle with tolerability. I am going to jump right on back of Neil's case. This is the 52-year-old. Some challenges with cardiovascular disease and they ended up being put on imatinib. This is an important clinical clue to how significant the patient's coronary artery disease was, that someone took a higher Sokal risk score patient and put them on frontline therapy with imatinib for the concern of cardiovascular. I want you to keep that in the back of your mind.

 

Unfortunately, this person has significant GI complaints related to imatinib. They are taking the drug. They are responding nicely. They hit their milestones at 3 months and at 12 months. Looks like they are a nice responder even to the first-generation drug. But having lots of GI problems, some peripheral swelling, significant so that they cannot wear the shoes that they like to wear. This patient's asking to change.

 

[00:44:27]

 

          Pretest 3

 

The question for the audience is, which TKI would you consider an optimal switch for this patient, known significant coronary disease, side effects of GI tolerability, and side effects of volume and fluid retention problems? Would it be:

 

1. Bosutinib;
2. Dasatinib;
3. Nilotinib;
4. High-dose asciminib at 200 twice a day; or
5. Ponatinib.

 

Please vote. It looks like asciminib and dasatinib look to be the choices. We will talk more about this one case later.

 

[00:45:27]

 

Intolerance vs Resistance

 

What is really vital to understand when you are talking about moving patients is there is a difference in how we approach this in patients who are intolerant vs resistant. You have to understand that most of the early studies with second and third-generation TKIs combined them, allowed people with both of these problems to be able to be enrolled in the study.

 

Intolerance is different in the fact that you have to understand how the intolerance is really impacting the patient day in and day out, to really get an assessment of whether it makes sense to actually move the patient.

 

When we talk about resistance, you are almost forced to move patients to a different drug when you find out that they have clinical resistance.

 

[00:46:13]

 

Understanding TKI Intolerance

 

The way I am starting to think about intolerances is this. I think about them as objective intolerances, ones where you are clearly worsening a comorbidity or you are clearly running into end-organ problems related to the drug. Then you have, what I call, the subjective ones. These are the ones that Neil mentioned the day to day annoying ones that are not necessarily super risky, but people do not feel well on their medication.

 

I am going to talk a little bit about some special intolerances, including pregnancy, the idea and financial intolerances, which I think come into play when we think about ways to approach treatments for second-line.

 

Objective tolerances.

 

[00:46:56]

 

Additional Factors to Consider in CML Treatment Selection

 

Well, again, I am going to show you this slide again. Neil went over it very nicely. But the biggest thing I think is the comorbidities. When someone is intolerant to 1 TKI, we have to go back and think about their comorbidities when we are thinking about which is the second drug we want to try. I think comorbidities plays a big role here.

 

I also want to talk about something different in patient goals. Not specifically can I get off drug or how am I going to live for a long time? But the unique situation where someone wants to start a family and they have CML and they are on a TKI.

 

Finally, I will briefly mention some intolerance from a financial standpoint.

 

[00:47:42]

 

More Than 50% of Patients With CML Have at Least 1 Comorbidity at Diagnosis

 

Comorbidities, are they common? The answer is yes. When people are newly diagnosed with CML or being treated with CML, there is a significant percentage of them that have meaningful comorbidities. If you look on the right, you will see that almost 30% or 35%, a third of patients will have 2 or more comorbidities that could impact their ability to tolerate their medicine, maybe even impact how long they can stay on the drug. We have to keep this in mind that significant comorbidities are common.

 

[00:48:18]

 

Treatment Options Based on AE Spectrum of TKIs in CML

 

Again, in looking and thinking about comorbidities, Neil has shown this slide. But it just goes to show that there are some classic untoward effects of TKIs that can fall into individual, specific drug side effects, as well as some common ones, which are probably class side effects.

 

[00:48:45]

 

Individualizing Targeted Therapy in CML Patients With Specific History or Comorbidities

 

Again, when you look at the slide that Neil showed, again, there are some well-described TKIs you want to avoid. The classic one is someone with COPD and could be really, really compromised if they developed an effusion. You might want to stay away from dasatinib, which in 100 mg per day dosing has significant rates of effusions.

 

If we look at the bottom of the slide and we look at coronary artery disease or cerebrovascular disease, the majority of the TKIs, all of them here are listed, except for imatinib, one has to be able to give patients very carefully, and you have to work really hard as an oncologist to help them minimize any cardiovascular risks that you can when you are using these TKIs.

 

Again, some well-described side effects that you want to avoid certain TKIs with.

 

[00:49:44]

 

Understanding TKI Intolerance

 

How about this softer one, this subjective one? We call it brain fog. We call fatigue. We talk about things that limit people leaving the house and they just do not feel like they can do the types of activities that they used to do when they are on these medications.

 

[00:50:00]

 

Patient Reported Symptoms: CML Patients on Long-term Imatinib

 

Well, this is a slide looking at long-term effects of imatinib. As Neil mentioned, this is 1 of the TKIs that people have lots of little bothersome things, not necessarily life-threatening. But if you look at the right side of the cartoon, and this is at 5 years on the drug, so people were managing to be on the drug for 5 years. A significant percent, over 80% complain of significant fatigue.

 

When you think about that, you realize that the subjective types of intolerances are very real and very important and ones we have to keep in the back of our minds when patients are on these drugs.

 

[00:50:45]

 

Strategies to Manage Intolerance

 

What are our strategies? Again, these are a big global broad statements. I am not here to tell you that if someone has lots of nausea, how to manage antiemetics? I am expecting the providers in the audience to be able to do that. But I think what is missed sometimes is managing the patient's expectations and actually telling them, “Hey, you need to be able to expect this. This may continue for a while. Over time, many of these side effects will slowly dissipate or get better, and you get used to them.”

 

When patients come in and they are diagnosed with a cancer and then they are told they are going to give a pill, there may imply it in their own minds that this is going to be pretty easy. I should be able to tolerate this pretty well. This is not a heavy duty chemo. But in fact, I think it is really important you have to let the patient know to expect there could be some side effects. Many of them get better over time. Some of them will not.

 

In that case, we are blessed with 6 different FDA approved drugs in the US. We have the opportunity to move people to different drugs if they cannot tolerate things.

 

[00:52:05]

 

Low-Dose Dasatinib vs Standard-Dose Dasatinib in Newly Diagnosed CP-CML: A Propensity Score Analysis

 

Now, the strategy before we get to moving around to different drugs, is this idea of maybe we could do some dose reduction. Or maybe the question is, is every TKI need to be dosed at full strength, at full FDA approved dosing? We know in many of our practices, most of our patients are probably not on the full labeled indicated dose.

 

I have been very interested in this, and this is 1 of the studies that I rely on a lot because it made me think. This is a work out of the MD Anderson, looking at a group of patients that they preemptively gave 50 mg of dasatinib to as a starting dose. They looked back in their database, and they found a group of patients that were started on 100 mg of dasatinib, again, the indicated dose for frontline therapy.

 

They did a propensity score analysis. What they did is they looked at these 2 groups of patients. They found 77 that matched up pretty nicely clinically with comorbidities and things. They asked the question, “Hey, how did people do when we started them on 50 vs 100?” This is not a randomized trial. This is not prospective. It was retrospective, they tried to match these patients to try to get some good data from it.

 

[00:53:26]

 

Low-Dose Dasatinib in CP-CML: Baseline Characteristics

 

Again, a very busy slide here. But on the middle grouping is the pre-matched information for the different populations, 50 dasatinib upfront vs 100. You can see the characteristics, age and spleen size and white count at diagnosis, blasts etc.

 

But if you look on the right and you look at the post-match, these are 77 patients in each group, you can see that none of these factors were statistically different. It looked like they did a very nice job in matching people to look at their outcomes and their how well they did on a lower dose of the drug.

 

[00:54:08]

 

Low-Dose Dasatinib in CP-CML: Outcomes

 

When you look at the outcomes from the standpoint of failure-free survival, event-free survival, overall survival and you looked across the board between the dasatinib 50 mg group and 100 mg group, they looked very similar. In fact, if you had to take a guess, at least from a standpoint of failure-free survival, it looked to be statistically different and it favored the lower dose of dasatinib.

 

When we looked at hitting milestone molecular endpoints, including complete cytogenetic remission, MR, MMR, MR4, MR4.5, again you can see that the groups were very similar in the success of this. In fact, when you looked at the deeper levels of response, the 50 mg group looked like it was very favorable.

 

In fact this raises the question of, how do we optimally dose patients? And is it always the highest dose of the prescribed dose? It may not need to be. I really like this study for looking at this. And I think we should be doing this with additional medications. There has been studies with bosutinib as well, again, suggesting that a lower dose may in fact have significant clinical benefits with less side effects.

 

[00:55:41]

 

Low-Dose Dasatinib in CP-CML: Safety (Postmatched Groups)

 

Again, here is the side effect profile from the matched groups. Again, looked very, very similar. Importantly, the last 2 on the list: kidney function favored the lower dose and effusions favored the lower dose. Again, it could be an improvement in tolerability and not without compromising the success of the survival and the molecular endpoints.

 

[00:56:06]

 

OPTIC: A Phase II Dose-Optimization Trial Evaluating 3 Different Starting Doses of Ponatinib in CP-CML

 

This is a study that many of you may know even a little bit better, but this is taking what many of us would consider the drug that has the most significant dangerous toxicities, which is cardiovascular events and vaso-occlusive events. This is ponatinib. They said, “Geez, this is a really good drug. We need this drug for certain patients, particularly those with the T315I, which renders the first and second-generation TKIs ineffective.”

 

At the time this study was done, this was the only drug we really had with activity against T315I. They developed a mitigation strategy. They randomized patients between 3 different starting doses with the idea that as soon as you achieved a molecular response of a PCR less than 1%, that you would then go to the lowest dose to try to maintain that response. They looked at patients with a T315I mutation, or those that were resistant to at least 2 or more TKIs.

 

[00:57:12]

 

OPTIC: ≤1% BCR::ABL1^IS at 12 Mo (Primary Endpoint), PFS, and OS

 

This again is a busy slide, but I want to just look at the top line in the orange. Those achieving 1% BCR::ABL at 12 months, and when you looked at it, the group starting at 45 mg and randomized vs 30 vs 15 as starting doses, achieved a 1% PCR by 12 months more frequently than the other dosing.

 

In fact, this idea of starting at a high dose seem to be important for the quality of the response. Survival was very similar between the groups. That is the bottom part of this table.

 

[00:57:55]

 

OPTIC: Effects of Dose Reduction on Response

 

If we look at the effect of dose reduction, what happened when we dose reduced once we hit that 1%? Well, it turned out that about 75% of patients that were able to achieve a dose reduction in the 45 and the 30 mg starting dose groups turned out to be able to maintain that response on lower dose.

 

If you look a little bit further down, when we look at the effects of what happens if you lose your response. When we look at the 45 going to 15 mg, about 60% of those patients, when they lost that 1% response, when you went up back on a higher dose, you could achieve that again. That number was almost 80% small numbers in the patients with 30 mg.

 

It looks like that you can maintain the best response with 45 mg if you are moving because of either resistance or T315I mutation. But you can develop a strategy to maintain that by dose reduction, knowing you could increase the dose if you lose that response.

 

[00:59:10]

 

OPTIC: Safety Summary

 

Then the question became, what about safety? Did it make a difference with safety? It looked like when we looked across the board, there was really very little difference in safety. Grade 3 or greater side effects were very similar between the 3 groups. Grade 5 side effects. Again, there were events in both the 45 and the 15 mg starting doses. There were strategies used to either discontinue, dose reduce or interrupt in order to maintain people on these medications.

 

It looked like that a way to manage tolerability and to mitigate the amount of time being treated with high dose look like this to be a very, very positive and favorable strategy.

 

[01:00:03]

 

5-Yr Follow-up From OPTIC Evaluating Multiple Reduced-Doses of Ponatinib in Patients With CP-CML

 

Recently or a few years ago, Jorge Cortes updated this with 5-year follow up.

 

[01:00:10]

 

The OPTIC Approach: Efficacy and Safety of Ponatinib Dose Optimization

 

again, I am just going to go to the slide on the left, which basically shows that the ongoing responses at 60 months compared to 12 months continue to be favorable across all 3 groups. Patients that are maintained on these continue to improve responses.

 

When you look at the adverse events, again, very similar between the group, very low rates of adverse events and, again, not unexpected. It appears that this mitigation strategy is reasonable.

 

[01:00:44]

 

Trials With TKI Dose Reduction or Intermittent Dosing

 

There are other types of mitigation strategies that have been tried. These are very interesting to me. This is the notion of whether or not we can take blocks of time off of TKI and maintain our responses. There is the INTERIM, the DESTINY and the OPTkIMA trial. Specifically looking at, for example, the INTERIM trial, it is 1 month of treatment, 1 month off, 1 month of treatment, 1 month off and see how people could maintain their response.

 

You can see that at 6 years, about 1 in 5 ended up losing either MMR or complete cytogenetic remission. This is significant. These are big losses. We are not talking about an MR4.5 going to a MR4, but we are talking about people losing MMR and even cytogenetic response on this type of strategy.

 

With the DESTINY trial, this was a dose adjustment. So going on lower doses and trying to maintain it. Again, 3 years into that, about 36% in the MMR group were able to remain on lower dose, but this was much higher, 72% in people in the MR4. If you have an MR4, for example, and you are doing well on therapy, and you want to try to minimize the long-term side effects of being on a drug, lowering the dose and continuing to follow people may certainly be an important strategy.

 

The last study gives us a little bit more advice on this block treatment, a month on, a month off, a month on, a month off, then maybe a month on and 2 months off or a month on and 3 months off. The message from this study, as far as I can think about it, is that the more time you are off of the TKI, the more likely you are to end up losing a meaningful clinical response.

 

While these treatments may lessen exposure to drug and hopefully ideally lower toxicities from the drug, one has to undertake these very, very carefully. I have not really adopted these in my practice yet. We are going to ask Jerry and Neil at the end of this how much they have been using the block strategies in their practices.

 

[01:03:17]

 

Strategies to Manage Intolerance

 

When to Consider Allogeneic Stem Cell Transplant?

 

It sounds weird to talk about allogeneic stem cell transplant when I am talking about ways to manage intolerability. But in fact, in the era of transplant mortalities that now is somewhere in the 5% to 15% or 5% to 12% range mortality. The question really has to come into play, when do we use allogeneic stem cell transplant for patients?

 

Again, it is the standard of care in patients who have blast crisis. If you can get them into second chronic phase, people should move to allotransplant as the best long-term survival strategy. But there are patients with intolerability such that they are on several different TKIs, maybe even all of the TKIs, and still remain with recurrent pancreatitis, for example, cytopenias that cannot be managed with growth factors and put people at risk for significant bleeding and or infections.

 

Every year at our institution, we take 2 or 3 patients to transplant because of intolerability. I put that on the chart just to make people aware that if someone is intolerant to 2 and 3 and 4 TKIs and it is recurrent and you are really struggling, I do not think it is at all crazy to be referring them to a transplant center, to have them at least talk to a transplant expert to let them know about the possibility of an allotransplant that we rarely, but sometimes do use for intolerability.

 

[01:04:55]

 

Understanding TKI Intolerance

 

Safety of TKI Discontinuation for Pregnancy in Patients With Established CML

 

Special intolerances. I had a great talk at our CML meeting, which was in Portugal in the fall by Jane Apperley. This is work from the UK and her group. They developed a registry to really understand this idea of pregnancy. I call it my special form of intolerability. But someone who wants to start a family. What do we do?

 

Now, in high-income countries, the age of onset is 55 to 60 for CML. Again, maybe not as common a problem as it is in low and middle income countries where the age is much younger from the standpoint of the onset of the disease. I do not know that I completely understand why. But these are the data that have been pulled together.

 

This question of how do you have a family and be on a TKI for your CML, is a really important one.

 

[01:06:01]

 

Pregnancies While on TKI: A Patient Cohort

 

They looked at a registry data and they came up with the 86 patients in a total of 122 pregnancies. These were data collected across 14 hospitals, again in the UK. They basically realized that a significant portion of patients, about 64%, had planned this pregnancy. A third or so were unplanned pregnancies. You can see that there were some women who had multiple pregnancies while being treated for their CML.

 

Again, when we look at the TKI that patients were on, again, pretty evenly distributed. Most of the patients were on imatinib, equally distributed between dasatinib and nilotinib and a few patients were on bosutinib, ponatinib or asciminib at the time of this.

 

The depth of responses were noted. MR4.5 or 5 about 30%. About a third of them were undetectable range. Another 20% were at MR4, and then the rest of the group were either MR3 or above.

 

What I found interesting, even though 65% or so of these were planned pregnancies, it turned out that stopping the TKI after their last menstrual period turned out to be, in the majority of patients, 55%. Again, it may have been planned in their mind, maybe the pregnancy happened sooner than they expected, but a significant number of patients were still on TKI at the time.

 

[01:07:47]

 

Impact of TKI Discontinuation on Established Response in Pregnant Women With CML: MR4 and MMR

 

When they looked at patients who had achieved an MR4 that is on your left. The idea of what was the likelihood you would lose that response by stopping at the time in order to proceed with a pregnancy. It looked like the deeper your response, MR4 vs MMR vs just a complete cytogenetic remission, you were more likely to hold your response the deeper you were when you started when you came off your TKI.

 

When you look at the curves on the right, and this is patients with MMR only. Their best response was a 3 log reduction. Again, you can see that the majority of these patients end up losing their response. The deeper your response going in makes sense, the more likely you are to hold it, at least during the pregnancy time period.

 

[01:08:47]

 

Use of Interferon During Pregnancy (All Pregnancies)

 

Some patients were treated with interferon. I just say this to remind people that we have talked about interferon for years as being relatively safe. It is natural. Your body makes interferon. In fact, there is not great data to know this, but they used it when patients lost complete cytogenetic remission most of the time, sometimes it worked to get them back into a complete cytogenetic remission. But what really worked to get people back into a response was restarting their TKI.

 

[01:09:19]

 

Probability of Regaining Response on Restarting TKI in Pregnant Women With CML

 

This is the probability of achieving and regaining a response when you went back on TKI. Again, similar to the treatment-free survival and treatment-free remission studies, when you stop someone in a deep response and you put them back on their TKI when they progress, the likelihood of responding is very significantly high. It happens very quickly. So there is a little bit of comfort in the background there.

 

[01:09:52]

 

Patients With Disease Progression or Death in Pregnant Women With CML

 

Not everything was a perfectly happy story. There were a couple of cases of disease progression. A couple of women went into blast crisis in their observational study. There were a couple patients who unfortunately died, 1 related to graft-vs-host disease from a transplant and had some problems with compliance issues. But in fact, we have to keep this in the back of our mind that all of this is not necessarily without bad side effects as well.

 

[01:10:28]

 

Infant Outcome (All Pregnancies)

 

When we looked at the outcomes for the children, again, most of the children, about 80% were delivered around their planned, gestational age. The birth weights were very stable and good. There were some fetal abnormalities that were noted. Several of them were cardiac. A couple of metabolic. Cleft lip palate, a neuroblastoma. There were a handful of untoward effects.

 

It is not clear if they are related to the TKI or not, but in fact, they were noted in this group of 84, 122 total pregnancies.

 

[01:11:12]

 

Infant Congenital Abnormalities (All Patients)

 

The 1 thing I will tell you as they broke down, and I am showing this for 1 reason, they broke down the cardiac, Poland syndrome, the metabolic problems and the cleft palate. The majority of the women were on TKIs for a significant chunk of time prior to the pregnancies that had these outcomes. So 7 years, 8 years, 15 years. So a significant time on TKI.

 

I am not exactly sure what that means, but that was the 1 thing I noted. There were a handful of people who were on TKI for some significant chunk of time while they were pregnant, so stopping the drug 17 weeks after last menstrual period, 16 weeks, 8 weeks, 12 weeks, etc. So a significant time period of overlap between the pregnancy and TKI. It is just worth noting.

 

Very interesting. We need more data to support this. I think there are ways to take patients off of TKIs with some comfort that when you start the TKI again, hopefully I will be following the delivery of delivery of a healthy baby that in fact you can get a good response and should expect a good response again.

 

[01:12:34]

 

Understanding TKI Intolerance

 

Finally, I will mention financial toxicities.

 

[01:12:38]

 

Annual Cost of TKIs

 

I stole this from Hagop Kantarjian letter a while ago. I tried to update it with my most recent Mark Cuban Cost Plus pharmacy data. These are significantly expensive drugs. That is just the way it is. The generics have made a big dent and really made it possible to treat with lower cost.

 

[01:13:05]

 

CML Prevalence in the United States

 

The implications of this, if you say yourself, there is 40,000-some odd people out there, the prevalence of this disease right now, and give yourself an average of $100,000 per patient per year, it is a $4 billion small cancer.

 

Then if you say to yourself, we do so well with this small cancer, that in another 25 years there is going to be 150, 160, 180 patients with this disease that we keep alive because of our TKIs. It is a significant amount of financial burden.

 

We just have to keep that in the back of our mind as well, because this is certainly important.

 

[01:13:48]

 

Suggested Approaches for Managing Treatment of Intolerance

 

Management of Treatment Intolerance in CML

 

When we talk about strategies to deal with intolerability, I will tell you that, again, you will see lots of little commentaries like these. I do not think there is any easy answer. You need to think about, most importantly is what is the patient's comorbidities? Is there a drug that might minimize the effect on the comorbidities in that case, when you are going to second-line because of intolerability?

 

We make a big deal of knowing the difference between resistance and intolerability. In resistance, we are often saying now it does not do you any good to circulate a second-generation drug. You should be moving to a third-generation drug if you are resistant to a second-generation drug. That does not hold for intolerability.

 

You can certainly stay within class or within group for tolerability issues.

 

[01:14:45]

 

Putting It All Together: Expert’s Approach and Takeaways on Managing Spectrum of TKI Intolerance

 

Some takeaways. It is important to recognize you need to change TKIs because of intolerability. You need to know the difference between that and resistance.

 

The objective tolerability seem easy: end-organ dysfunction or worsening of comorbidities. Subjective ones are subtle. I think it goes a long way to recognize it and manage patients expectations and let them know this could happen. You could feel tired. You may have fatigue issues, sleep issues, other things because that actually helps people manage it. I really do believe.

 

Pregnant patients, another very interesting intolerability from my standpoint. We are gathering more and more data over time that it is possible to manage people and support people through pregnancies. There is a significant economic implication. Everybody in this room understands it. I just wanted to recognize it.

 

[01:15:41]

 

Abstracts of Interest at ASH 2025

 

Some abstracts of interest are looking at different dosing strategies, tolerability for long-term ways to manage that as well. Again, difference in dosing etc. that may impact it. These are some ones to keep your eyes out for.

 

[01:16:01]

 

          Patient Case Continued: 52-Yr-Old Experiencing AEs on imatinib

 

We will just go back to our case and I will ask you the same question.

 

[01:16:03]

 

          Posttest 3

 

When you want to move to second-line on this patient with significant cardiovascular problems and on imatinib frontline therapy and responding, what would be your choice?

 

1. Bosutinib;
2. Dasatinib;
3. Nilotinib;
4. Asciminib twice a day; or
5. Ponatinib.

 

A significant number of patients ended up picking asciminib. The reason that was not correct, that was on the high dose of asciminib. A little bit of a trick. That is the dosing for T315I vs AD. I ended up picking dasatinib as the 1 I would use. The truth of the matter is I might even use dasatinib at 50 mg because the patient is already responding in an MMR, at the time I am seeing them, and I am switching them for tolerability. You probably could get away with even a lower dose. Even my answer to the question may not be perfect.

 

[01:17:27]

 

Q&A

 

With that, we will see if there is any other questions. But I wanted to ask both Neil and Jerry about how they specifically approach a transplant for intolerance. Not for resistance, but for intolerance. Jerry, do you have any thoughts about how you do that at Seattle?

 

Dr Jerald Radich (Fred Hutchinson Cancer Center): Yes. We used to transplant before TKIs, like 140 CMLs a year. Now I would say we probably transplant 5 to 10. About half of them are blast crisis. The other half are intolerance. Because if you just cannot give anyone a drug, you are not doing them any service by letting them just eventually go into accelerated or blast crisis.

 

You have to realize that now everyone has a donor pretty much, if you look at siblings, unrelated donors, cords and [?]. All of those survivals for all the other acute leukemias are identical with those different approaches. For years, transplant results for chronic phase is going to be 85% or so of survival. There is no reason to wait on these people if you cannot get them effective drug, if they are the right age and the like.

 

Right now age categories. We usually go with reminder store, reminder turned 90. We really do not have age upper limit anymore. Yes, we would go.

 

Dr Smith: Your program still transplants for intolerance?

 

Dr Shah: We do. I mean, I do not transplant myself, but I do always try dose reductions. But 1 thing to keep in mind about pretty much all the available TKIs is that they are metabolized through CYP3A4. There are people who have polymorphisms in whom you just a whisper thin dose. Their disease responds, but they fall apart.

 

One thing that I am holding out some hope for on that front is the Enliven drug, because it is my understanding that that is not metabolized through that pathway. It remains to be seen if some of these people may be sensitive there.

 

Dr Smith: With that, I will welcome Jerry Radich for the third part of our session.

 

[01:19:42]

 

Optimal Risk Assessment, Response Monitoring, and Testing for TKI Resistance in Patients With CP-CML

 

Dr Radich: Well, that was 2 outstanding talks in a row. I note that the bars are open. This might be a good time for you to partake of them. Neil put it on his tab, so he is buying. Feel free. I would not be distraught if you do that.

 

[01:20:05]

 

          Pretest 4

 

We are going to go to a question here. Which of the following would cause you to investigate a potential therapeutic change in someone who has been receiving 400 mg of imatinib with no tolerability issues?

 

1. BCR::ABL of 5% at 3 months;
2. BCR::ABL of 1% at 6 months;
3. BCR::ABL of 7% at 6 months; or
4. BCR::ABL of 2% at 12 months.

 

Okay. Well, some of you got it right. Some of you got it wrong. I will leave you in mystery and see how we perform at the end.

 

[01:21:04]

 

          Patient Case Continued: An Update

 

Here is our 59-year-old that we are still following. She has now been receiving asciminib for about 72 months following a previous switch. Her last BCR::ABL reading was 0.012. She is worried about financial toxicity, which Doug talked about, and she is thinking about TFR and asks what the next steps will be.

 

[01:21:25]

 

          Pretest 5

 

Which of the following patient conditions meets the criteria for considering TKI discontinuation and attempting TFR? You have 4 choices. You can read them as fast as I can say them.

 

Again, we did pretty well. I will go through and hopefully we will improve it a little bit.

 

[01:22:12]

 

The Impact of TKIs in CML in 4 Graphs

 

Neil has shown some of this before. This is the impact of TKIs in 4 graphs. Three of them he showed before here, the old progression that was inevitable with everyone who did not get TKIs. The astonishing increase in survival which makes us the poster child of all things in precision medicine. The fact that people now have essentially a normal lifespan is just unbelievably remarkable.

 

This is the results of discontinuations, which are surprisingly effective because I think when we first started doing this and the particular religion of CML stem cells and the like thought that they would have to be always inhibited that you would not be able to get away with taking drugs off because you would already have a reservoir that would pop up again. That does not seem to be the case in a lot of patients.

 

[01:23:05]

 

3 Big Questions in CML Treatment

 

Now there is 3 really big questions in CML that you can look at graphically. First is who responds to therapy? Why do people go that side vs that side? Who relapses after therapy? Why do some people come back out of therapy and some remain in deep response? Who can discontinue therapy? Can we predict who, when you discontinue therapy, will keep doing that vs those who will relapse?

 

Because obviously if you could know upfront which patients were going to relapse after you discontinue therapy, you would not expose them to the possible ability that they would have unopposed inhibition of BCR::ABL and potentially go into progression.

 

[01:23:45]

 

Blast-Phase CML (MPN/MDS/AML)

 

This is a slide that I stole from Nick Ross[?]. One of the themes that we talk about is the overlap of response and progression in blast crisis. There are some similar biological pathways that happen through those.

 

The usual old school was that you went into chronic phase. Then going into the blast crisis, you would accumulate other cytogenetic abnormalities, other gene expression abnormalities and other mutations. We now know there is also, in the background, clonal hematopoiesis going on. So you can accumulate some mutations prior to presumably going into BCR::ABL.

 

As I will show later, CHIP is not just these mutations, as it turns out that there is basically all of these can be found in here. That makes our interpretation of next-generation sequencing data a little bit problematic. And I will show why.

 

[01:24:41]

 

          Monitoring Response to Achieve Key Milestones in CML

 

Here is where we started. I think just for entertainment value, if not anything else, it is understanding how this curve came apart. This is from our initial analysis of the IRIS data, looking at BCR::ABL at 12 months and finding that if you had a 3-log reduction, you did exceptionally well compared to the curves that did not have a 3-log reduction.

 

The 3-log reduction has no biological rationale at all. How this happened was we had a call during IRIS. The 3 labs that were responsible, my own, Hammersmith and Tim Hughes in Adelaide. Because the time differences, it was always 2:00 in Seattle. So I remember this very well.

 

We were getting the data together to get ready to publish. We were looking at the survival curves and we noticed that there was a break in the survival curve when you looked at this 3-log reduction at 12 months. We said, well, that is interesting. I do not know why that would be, but we will just ad hoc say that is a cool thing and throw it in the New England Journal.

 

We said, “Well, we have to have a name.” I think it was Tim that came up and said, “Well, why do not we call it major molecular response?” So we never expected it to last. We thought it would be a cool term. But it turned out that in many, many studies, it really does have biological impact. We do not understand why that level of response makes a difference. But it really did stick.

 

[01:26:11]

 

CML Response Criteria

 

There is various ways that we can measure response, but now it has all evolved much towards the molecular status. Einstein said, “Never memorize anything that you can look up.” So I would not go through all this stuff here. Basically we expect everyone to go into hematological response nowadays, which is just normalization of their white counts.

 

Cytogenetics, we do at diagnosis to see if anyone has any additional clonal abnormalities. But pretty much in the developing world, once you start on therapy, almost no one gets a cytogenetic response again. These old major, partial and minor have been exhausted out of my memory. But we do use molecular response.

 

The major ones that we are concerned about these days are early molecular response, which is more or less than 10% at 3 or 6 months, and I will talk about those differences. The major molecular response, which translates into 0.1%. That is about the level where cytogenetics become negative. That is a stand in for cytogenetic remission.

 

In deep molecular response, which is defined at anything of 4.0 reduction of the BCR::ABL or greater.

 

[01:27:23]

 

Prognostic Implications of Select Cytogenetic and Molecular Responses in CML

 

These makes some difference. The major difference in how people do, meaning the major difference in overall survival is whether you get a complete cytogenetic remission or not. At a level of 0.1 or 1% is basically the cutoff. If you do better than 1%, you have gotten all the survival benefit you are going to get out of it. Everything deeper than that is gravy.

 

If you get down to 0.1%, we say that MMR is a safe haven because at that point, progression or relapse is really pretty unusual. If someone does, you have to really start thinking about whether they are taking their drug or not.

 

Then the deep molecular response is important. In this early molecular response it is important because the early response is a predictor of late response, that makes complete biological sense, right. People who have early molecular response do better overall survival and progression-free survival than those who do not. That can make complete biological sense.

 

[01:28:33]

 

Guidelines for Monitoring Response to TKI Therapy and Mutational Analysis in CML

 

We have criteria from the ELN and NCCN about how often you should do this, again, cytogenetics really at diagnosis. Really the only time you have to do cytogenetics after that is if someone fails to mount milestones. Even then if someone has a small bump in their BCR::ABL and you are thinking about changing drugs. Unless some of the things are changing, I do not really feel strongly that you really need to do cytogenetics to that point.

 

qPCR, we do quite frequently. We probably actually do this more frequently than we need to. I say that because I work with the Max Foundation that does international studies of TKIs and their patients who have been on drug have the same survival as people in Seattle, and they barely get monitored. So I think we probably overkill the monitoring. That is bad for me to say because I wrote the NCCN guidelines for monitoring. So bad me.

 

The mutation analysis really we do when people have either not respond to therapy at all or have hit a milestone and then bounced out of the milestone. You see something going wrong. Why are not they responding to TKIs anymore?

 

[01:29:45]

 

Value of Milestone Achievement in CP-CML

 

You have seen these before. These are the cautionary notes based on the stop signals. These caution things, this is an ELN flavor. You do not do much for caution except worry. I worry too much as it is. I just think about, like, why do we need to change drugs? Why do we need to change drugs is if they have a greater than 10% at 6 months, and then we think about possibly changing them if they are above 1% at 12 months and on.

 

[01:30:19]

 

Outcome by BCR::ABL1 Response at 3 Mo and 6 Mo

 

Now, 1 of the reasons that we think about 3-6 months, you have to realize that especially in industrialized world, most of the people with CML when they are diagnosed are picked up by happenstance insurance, physical exam, etc., pre-op studies. They are not really sick with their disease. Anything we do to them, no matter how benign the drug is, is we make them sicker than they were when they were diagnosed.

 

Often adherence to therapy early on is a problem because you are trying to bounce around their drug with their toxicities. Often by the 3-month mark, people have not figured out how they are going to deal with their drugs and their side effects and a lot.

 

If you tied someone into a chair and gave them drug for 3 months, and they did not have a good response, then you could say, “Okay, they are definitely it is biology.” But without that, you have to wonder whether or not some of this has to do just with adherence.

 

This is a great example of this. This is data from Adelaide that Sue Branford gave me. If you look at the best case scenario, it is this person here. Three months, they have got less than 10%. At 6 months, they have got less than 1%. That is like ideal response. They have got fantastic progression-free survival, freedom-free survival, MMR rates of 88%.

 

Look at this one. This one is greater than 10% at 3 months. At 6 months, they are suddenly less than 1%. That has got to be intolerance or adherence, right? I mean, the biology of the disease does not suddenly say at 3 months, “My God, I am supposed to be responding. What was I doing?” And should not change.

 

This is someone who is now taking drugs and everything. Their response is fantastic. It is the same as this one up here. The bad one is this one, greater than 10%. Their chance of an MMR is only 3%.

 

Now, you still cannot exclude the fact that this may be someone who is just not taking the drug at all. But you would certainly think that this is probably more of a bad biology.

 

[01:32:23]

 

The Importance of MMR and DMR for TFR 

 

We are interested in getting into deeper responses, but that takes time. This is again stolen from Sue. I am looking at your rate of MMR of 4 logs or 4.5 logs at 8 years. For half of your patients to get to that response, takes some patience.

 

Then this is a landmark analysis about what happens if a person gets to various levels at 3-year mark. If you are at MMR at 3 years, your chance of getting into MR4.5, which will be deeper is almost 100%. That makes sense. You biologically responded to disease. You have proven that.

 

If you are an MMR, but not quite to M4, makes sense. Only about half of those people get there. If you have had just no response at all, this is a person who is less than MMR. Their chance of ever getting to 4.5 obviously is pretty low. So early response predicts a response.

 

[01:33:24]

 

Potential Predictors of Response

 

Now we do a lot of invention in our lab of devising new devices and the like. One of the things we try to think about what is the perfect device. The problem was discussed by 2 of my favorite artists, on the left here, Jim Jarmusch, who is a film director; on the right, Tom Waits, a singer. They are both idiosyncratic tastes. They both have great hair.

 

What Jim Jarmusch apparently said to Tom Waits, was fast, cheap and good, pick 2. If it is fast and cheap, it would not be good. If it is cheap and good, it would not be fast. If it is fast and good, it would not be cheap. Fast, cheap and good, pick 2 words to live by.

 

That explains all of the biomarker worker. I have layered them out here about how they fit. We will talk about genomic markers of disease response. That is not fast. That is not cheap. It is probably pretty good. Gene expression profiling is not fast. Relatively cheap. Might be good. Immune function composition tests, we will talk about.

 

Fast, yes. Cheap, no. Good, maybe.

 

[01:34:44]

 

The Molecular Heterogeneity of CML

 

There are, as Neil pointed out, certain constitutional genetic abnormalities that have been associated with different types of response. Again, I would not go through all of those. They have not really come to clinical practice reliably yet for a variety of reasons.

 

[01:35:01]

 

3 Pretreatment Factors Are Associated With Extreme TKI Resistance and Future Blast Crisis

 

There are some newer ones. We have spent a lot of work doing gene expression, which is pretty good at both defining progression and looking at patients from the get-go. If you look at patients when they are newly diagnosed and look at the best responders and the poorest responders, there is some bright gene expression signature that is involved with that. Curiously, pretty much the top 20 pathways and the top 20 genes that are involved in good response are from inflammatory and immunopathways.

 

It is all inflammatory and immunology driven. Then you can see an increase in signals that are basically T cells and NK cells. This is data done by our colleagues in Singapore who is trying to use that data to make a faster test with basically monoclonal antibodies and flow cytometry.

 

It basically has picked out markers from the inflammation pathways, some lineage skewing myeloid vs lymphoid and NK cells. In this paper, they can stratify people. It is pretty preliminary data, fairly well just based on a 5 color panel of flow antibodies.

 

[01:36:19]

 

          The Molecular Heterogeneity of CML         

 

Neil showed this earlier. This is data from the Adelaide group. We used to think that CML was a uniquely homogeneous disease defined and driven solely by BCR::ABL. That is probably because we were not looking. Now that we can look, we find that there actually are a number of changes. This is from the Adelaide group. Again, Neil had shown this before showing that a fair amount of patients, at least 20%, have other mutations, and many of them have other Philadelphia positive rearrangements if you do the RNA-Seq.

 

[01:36:54]

 

BCR::ABL1-Independent Somatic Mutations CML

 

If you look at independent somatic mutations in CML, 20% to 30% of people with newly diagnosed display intrinsic or acquired resistance to NK, KD domain mutations, at least half of them acquired resistance. But new mutations show up in similar to 20%, 30%. ASXL1, as Neil mentioned, various papers from 9% to 17%.

 

[01:37:20]

 

ASXL1 Mutations and Outcomes in CP-CML

 

Do these make a difference? They probably do, at least ASXL1, for reasons we are not quite sure. Neil has shown this already. This is a freedom-free survival, 81% for patients who have no other mutation. The bad group here is the ASXL1 mutation, which is substantially worse.

 

[01:37:42]

 

Impact of Mutated ASXL1 at Diagnosis by TKI

 

This is looking then at ASXL1 by diagnosis by what type of TKI you use. If you use a second-generation TKI, concentrate on the ASXL here. That is this 1 here. It is worse. FFS, worse. This is an interesting point that I will show more of. It is for some reason having a ASXL1 mutation and having an acquired ABL kinase domain seem to be more than just chance.

 

No doubt, however, that it was asciminib. Not so good with the ASXL1. The FFS here with other TKIs like there, there is ASXL1, and there is ASXL1 and acquired ABL kinase domain. Again, mechanism of this yet unknown, and we need bigger studies to really prove it is the case.

 

[01:38:35]

 

Mutational Spectrum and Frequency at Resistance

 

But this is an association from real-world data. Now, what we do in our lab is we do a lot of stuff with low and middle income countries, where if you can get us samples. Typically, we do this on dried blood spots now. We can do BCR::ABL. We can do ABL kinase domain, and now we can do the whole 200 gene battery. If people send them to this, we will do it for free.

 

This is 200 patients that came to us from various countries in Latin America, Asia and Africa. The only criteria was they just had resistance. We do not know what drugs they are on and the like. These are patients who just had been on therapy now and are resistant. There is no academic selection at all. This is just what comes through the door.

 

About half of them have mutations. Many of them have 2 or more mutations. What is curious is that here is the ASXL1 mutations here. These are patients who also have an ABL1 mutation. About half of the patients with ABL1 mutations have a coexisting ASXL1 mutation. About 25% of patients who are ABL-negative.

 

Again, we do not know chicken and egg. We do not know if the ASXL comes first and then acquires or vice versa. We are going to be doing some single cell stuff to try to sort that out.

 

[01:39:56]

 

Testing for TKI Resistance Mutations

 

Testing. That is the upfront stuff. Now you have got the curve where people have become resistant. This is like one of the first curves that Simona Severini showed. This is before other day of secondary TKI. People had imatinib. The drug failed them with mutations, what happens. It showed that for people who failed drug, they went into blast crisis and died pretty quickly. That is because what we were talking about is there is a gene expression pathway between resistance and progression that overlap quite a bit

 

It is not like people when they responded to therapy and then relapsed, we are back at square zero in early chronic phase again. They had a different profile.

 

You can go to these heat maps and figure out based on what your mutation is, what drugs you might be better served.

 

[01:40:48]

 

When to Consider Changing Therapy in CML

 

The question then again is like, when do you use this? How do you change therapy? We talked a little bit about that before, but I want to talk about warning. But in the failures are when we are thinking about this, when people have like either gotten greater than the 10% cytogenetically or they have lost response with a mutation.

 

[01:41:09]

 

Optimal Timing of BCR::ABL1 KD Mutation Testing

 

This is the scheme of the timing that you can think about using. You can look at 3 months and if you are less than 10%, you cannot do anything. But if you basically fail these criteria, then you do the tyrosine kinase mutation.

 

[01:41:26]

 

Mutational Analysis of the BCR::ABL1 Kinase Domain

 

There are specific mutations that map with drugs that you can use. I must say that in doing this, there is a number of times when people are referred to us who have switched from 1 drug like imatinib to dasatinib. They have sent away their sequencing. We see them after a month or 2, they are responding to dasatinib. You get back the data that they have a mutation that should not be responsive to dasatinib, and vice versa.

 

We get people who should be responsive and do not, which just shows again, this is probably a much more complexity than just meets the eye with these mutation analysis. But they can at least help drive your first call about what drug you go to in a pinch.

 

[01:42:12]

 

Summary of the Main Advantages and Disadvantages of Old (Sanger Sequencing) vs Newer NGS/PCR Techniques

 

Now, in regard to sequencing, there is various ways to do it. The standard way that we do it is with so-called Sanger sequencing, so direct sequencing. The sensitivity of that is about 10% to 20%, meaning if your allele information goes below that, it is hard to pick up. The advantage is it can be done in many places and with a relatively quick and cheap turnaround time.

 

There has been some work done with mass spectrometry. It is pretty expensive. It is fast, but it just has not taken off because a lot of people do not have clinical mass spectrometry sitting around to develop the assay.

 

ddPCR, we will talk about in a minute. What has come on mostly now is next-generation sequencing, which gives you a variety to look at multiple targets at the same time.

 

The limitation of next-generation sequencing, it is well beyond the sensitivity of Sanger sequencing, but it really has a lower threshold of around 1%. That is because when you do next-generation sequencing and you make the libraries, there is an inherent error in the transcriptase that does that. You will always pick up noise and that error rates about 1 in 1000.

 

It is higher if you do your sequencing off of mRNA, which a lot of people do for BCR::ABL. They take their mRNA. That is left over. They sequence from it. But reverse transcriptase is very dirty. We have calculated that. If you do that from mRNA, you make an error in a relevant gene in about 1 per 21 molecules you make.

 

By doing that, a lot of the stuff that is out there in the literature is probably background error because you are generating a sequence of the mRNA.

 

[01:44:06]

 

Lessons From the NEXT-in-CML Study

 

But it does seem to be better. This is a study from Simona, where she looked at patients who were resistant and found that 25% of them had a ABL kinase domain mutation by Sanger sequencing. She then did next-generation sequencing to the same samples and found that she found mutations below the level of Sanger in about another half. You basically boosted your signal by 50%.

 

[01:44:37]

 

Example of Potential of Greater Mutation Sensitivity

 

This is an example of why it might make some difference. This is a patient whose BCR::ABL is perking along during imatinib. This is the level of Sanger sequencing. They picked up these mutations that were missed by Sanger sequencing. Those come up. You could have gotten back here through your drug here. 359 mutation was down here below and that pops up.

 

What she found was that basically all mutations that she could look at here that made sense, would eventually come up.

 

[01:45:17]

 

Sensitive NGS Can Detect Mutations not Relevant in TKI Resistance and Response (CHIP)

 

This is another slide I stole from Sue. Now, this is relevant because as we start looking at more and more mutations, we are going to pick up background mutations that may or may not have to do with the CML clone. The question is, how do you use that and do you panic or not? The answer is no, do not panic.

 

Here is an example of a patient who has BCR::ABL going down like this. They have at that point low levels ASXL and TET. This is what those fish pots. The BCR::ABL clone goes away, the TET pot goes away or the ASXL. But here the TET expands.

 

The question is if you are doing sequencing of this, do you panic or not? The answer is no. That this is probably a background clonal hematopoiesis that is popping up. You have to use this stuff in the context of what your BCR::ABL is doing. If it is going in the opposite direction, it is probably not the BCR::ABL clone. Maybe some other clone, but it is not the BCR::ABL clone. So you do not need to talk about changing TKIs and the like.

 

[01:46:31]

 

CHIP Is Not Just “DTA” Mutations

 

Now, why this becomes important is, as we get to more and more sensitive sequencing, we are going to see a lot more of this stuff. This is a paper that has no immediate relevancy except for the point I am going to show. This is a harebrained thing we did. We had multiple pairs of patients who have gotten a transplant and have lived 20, 30 years.

 

The idea was, well, can we use that as a way to study clonal hematopoiesis? The idea is if I have, let us say, CML or ALL or any disease, and I am going to get a transplant, I have got 2 of my brothers here are going to be my donor. We could vote for who it is. Actually you wore a tie, so Doug is going to be my donor.

 

The hypothesis was, if I get Doug's stem cells, it has to go through about 30 replicative cycles to populate my marrow and give me hematopoiesis. There should be a lot of selective pressure in that. I should be accumulating more mutations and the like. Then if I measure my donor hematopoiesis or my donor clonal architecture 20 years from now and follow Doug's 20 years from now, they should be on different trajectories. Like there should be a completely different types of clonal architecture between those.

 

That is what we bet on. Most ideas are wrong. This was wrong too. How we did this was by a special type of error corrected sequencing where I said, you start introducing the limit of next-generation sequencing as 1 in 100, 1 in 1000. This has a theoretical level of 1 in 10 to the seventh. You can really pick out really very rare clones.

 

Just part of this paper that was interesting is that this is donor VAF. This is the recipients. So this would be me, and this would be Doug. You can find that we were completely wrong, that most of these clones stay relatively the same. There is like a clonal memory that goes on, which is wild. There is some clones that expand there, there, there.

 

What I want to point out is that these are all the clones that we found in donors, and we find these even in 10 year olds. These are not just the typical DAT stuff that people talk about. These are KIT, these are IDH1s, these are NPM1s. These are p53s.

 

As we get more and more sensitive sequencing, you are going to find all of these clones in patients that are going to really scare you. We are going to have to learn which of those are actually useful to follow and which of those are complete noise. But it is going to make life interesting.

 

[01:49:26]

 

Statistical Model of TKI Response

 

Lastly, what I want to talk about is stopping therapy. When Francois Mahon first proposed to stop therapy, he had a patient, the people who are BCR::ABL for years, and he was going to stop therapy. A lot of us thought that was a nutty idea. Turned out to be a brilliant idea.

 

Because when you look at these trajectories and you plot how long it would take to extinguish all of disease and therefore be cured, it takes a long, long, long time. We thought no way that is ever going to happen.

 

[01:50:05]

 

Selected Larger Clinical Trials of TFR Relative to Depth and Duration of MR: Completed Trials

 

We were obviously wrong because there is tons of trials now that have shown that you can discontinue with therapy and roughly half the patients will stay in remission.

 

There was a question earlier on about whether or not TFR pertains to patients in low and middle income countries? It does. We have got a study now that we have sent into New England Journal of Medicine. If any of you guys have any bite there, throw us a bone.

 

It shows that basically for well-selected patients in low and middle income countries, you have exactly the same results. So it is really game-changing.

 

[01:50:47]

 

ddPCR Increases BCR::ABL1 Detection Sensitivity

 

You obviously want to predict who is going to respond or who is going to basically stay in TFR vs who is going to relapse? Because you would not want to expose them if you did not have to.

 

One way for those patients who have been PCR negative is, well, if you build a better mousetrap, are the people who relapse just those that you could find with a more sensitive test? How people are doing this now is by digital PCR.

 

Just 2 seconds on what digital PCR is. As the name confers, you are basically calling a signal positive or negative, yes or no. How you do that is the concept is you basically take your BCR::ABL molecules and you partition them into wells. These can be physical wells, which is what Fluidigm uses. These could be bubbles, which is what Bio-Rad uses. But you do it so that on average there is well less than 1 molecule per bubble. Because what throws off the calculation is if you have multiple things in 1 bubble.

 

You can do it various ways and you basically count yes or no positives. For those of you who are fans of math history. I mean, really, who is not? The Poisson distribution was invented to describe the non-parametric curves of rare events. That is what you use to calculate these calculations.

 

This is the first published use of the Poisson distribution. It is the number of deaths by mule kicks to Prussian military officers in 1860. If any of you go on a game show and they ask you that and you win, I get half the money. This shows that it actually works. These are patients who have had, from the last study who before discontinuing drug, you basically do their PCR so you can do RQ-PCR. And if you also did ddPCR on the undetectable know, very few of those relapse.

 

If you are RQ-PCR detectable, that is your relapse rate. But if you are RQ-PCR negative and you are positive by dd, you are there. It really adds a fair amount of value to who is going to relapse and who is not. If you want to just do a test at baseline in the 3 months early to pick it up early, if you are positive at both time points, that is your relapse rate. If you are negative at both time points, that is your relapse rate.

 

If you want to try TFR for just a short period of time and then decide to stay on or not, at 3 months, you can pretty much pick who is the winner and losers are going to be.

 

[01:53:26]

 

ddPCR Model of TFR

 

This is just a meta-analysis of a bunch of data, showing again, that you can look at digital PCR, the duration of treatment and their transcript type, and get into a score and predict who has got a really reasonable chance of getting out and who does not.

 

[01:53:40]

 

Clinical Care Options CML Monitoring Tool

 

With that, I am going to keep on time and have you folks scan this for the nth number of times today.

 

[01:53:48]

 

Putting It All Together: Expert’s Approach and Takeaways on Monitoring CP-CML Response to TKI Therapy

 

We can see about our takeaways. First is that milestones are important. The reasons you cannot reach milestones, some of them are between the patient and the physician and adherence. Some of them are biology. You should match the response milestones with the treatment goals, meaning, if you are my age, all I want is to get into a value of a complete cytogenetic remission because that is where all the survival is.

 

If I am 20 years old, I want to get into a DMR and get off drug, right? You just have to have that conversation with your patient.

 

Resistance is a road to progression. We wonder sometimes if resistance is forever. You certainly have to take people who are resistant seriously and I think monitor them obviously more closely than the average pair.

 

The third thing, will we really run into TFR problems are those who, in retrospect, you look at and you look and say they never should have been attempted in the first place. They get impatient, they have a great response for a year and then decide to get off and the like. So really be careful about who you bring to this.

 

[01:54:59]

 

          Posttest 4

 

Revising the questions. Here is the first question again. You can answer it now and we will see how you do.

 

We should have an answer. You guys have gotten this. You have gotten slower. Here we go. The right answer is 2%, and I do not see the values. We learned something. Excellent. Thank you. I can go home in peace.

 

[01:55:58]

 

          Posttest 5

 

Next question. Well, I gave you the answer. So no one can get this one wrong.

 

[01:56:30]

 

          Poll 4

 

We have time for this stuff now. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No; or
3. Uncertain.

 

Always uncertain. Well, apparently the system is not working. We will have to assume that you are all going to change in a good way.

 

[01:57:41]

 

          Go Online for More CCO Coverage of Chronic Myeloid Leukemia 2025!

 

I have no other things up here. There we go. You can read this yourself. Go online for more information, downloadable slides, etc.

 

With that, I think we are done with exactly zero time remaining. If there is any other questions? Do you have any questions on here before we want to go through?

 

[01:58:05]

 

Q&A

 

Dr Shah: Just maybe 1 or 2 quick questions. A question came through about NGS sequencing. Are you a proponent of it, like a diagnosis? Why or why not?

 

Dr Radich: Yes, that at this point, I think the information is enough that we should be accumulating it on patients routinely. Because I suspect it is going to be written into the standards pretty soon, especially the ASXL1 stuff. We need to have more information to know how to use it.

 

I think especially, it may not infer your first drug choice, but certainly if someone did have like an ASXL1 mutation, you might be worried and be following them more carefully and be more inclined to use a second-generation drug but not asciminib.

 

Dr Shah: Yes, the NCCN guidelines have been updated to recommend that at diagnosis.

 

Dr Smith: Another question that came through regarding, combinatorial. Using combinations of TKIs. I do not know, Neil, you have studied some of this in the lab and things.

 

Dr Shah: Yes. Obviously, there is reason to think that you could use an allosteric inhibitor in conjunction with an orthosteric inhibitor. There have been some trials ongoing to do this. There are 2 potential benefits. One would be that, you could hopefully suppress more mutations that way. Another is you could maybe put more pressure on the disease and drive the disease burden down lower.

 

Obviously, a potential concern is toxicity and potentially cost, but there are trials going on to do that. We have never had the opportunity to really do that before. I think following some of these trials, the data so far are really very preliminary and small in number. But I think it is an interesting area to keep an eye on.