Management of chronic myeloid leukemia (CML)

DR MAURO: We’re here with Research To Practice talking about CML, which has a fantastic new era that we’re in really for CML. And this slide really just summarizes how this treatment for CML has evolved through the ages. We went from a period of chemotherapy only with, unfortunately, a very predictable prognosis which is fairly dismal, some improvements with interferon.

We then saw the advent of stem cell transplantation, and to be honest CML was a disease that was often viewed as the ideal condition for which transplant could be utilized. And it clearly changed the natural history but still left many patients without that option, with, unfortunately, bad outcomes. And you can see on top, at least the first 10 years roughly of what TKIs have done for CML and I think that really speaks to how we have a new day and a new era in CML.

CML Is really a survivable cancer nowadays. This is some data showing that the natural history of CML for patients of any age is that of a normal population, meaning the CML patient’s lifespan should approximate age matched controls without leukemia, whether they’re 40, 50, 60, 70 and beyond. And we also see that the prevalence of CML, the number of cases that we’re going to be needing to manage, that we have the great problem that patients are surviving CML. So, what was, for example, steady state incidence in the US of about 25,000, is going to be upwards of ten times as many by the middle of this century. So I think, again, a great problem, plenty of patients doing very well with CML.

And that really just builds on the history of CML. There’s some interesting and colorful early history the way CML was discovered and really then, I think from a pretty early point, 1960, when the Philadelphia chromosome, the first genetic abnormality linked to a cancer in humans was identified by a very simple observation of an abnormal chromosome in the blood of patients with CML, an abnormal chromosome 22. And then a very simple straightforward observation by cytogeneticist, Janet Rowley, showing that it was actually a translocation between two chromosomes. And from there, the pace picks up where we had identification of the genetic fusion elements, the activity therein; what happens with fusion. And then the thought that targeting a genetic fusion, if it’s a sole anomaly in a cancer, could that be attenable treatment for cancer? And my mentor, Brian Druker, back in the late 1990s, really brought the first drug into clinical trials after very sound, preclinical work and partnered with people like Charles Sawyers who is here with me at MSK and clinical trials for CML patients began with the — at this point we have now five FDA-approved drugs, one building on the other to improve the response, tolerability, manage resistance and high level resistance.

There are now generic forms of therapy for CML. And we have new drugs on the horizon, a particularly one called asciminib, which I’ll share some data with you in a little bit.

This is the spectrum of CML drugs looking at it from a Goldberg perspective, there’s not just the five approved drugs, there are even drugs approved outside of the US, for example, radotinib, which is a drug developed and licensed in South Korea. And I only include ABL-001 as a drug in development in the alternate third-generation or fourth-generation class, but there are several others. I’ll just list them by name: HQP1351 from Asia, K0706 or vodobatinib, coming out of India and PF114, another drug similar. These are all drugs that are very much like ponatinib, but may offer better tolerability and good efficacy, and that drug’s from Russia. So we have partnership around the global level to better treatment options for CML.

So in the US though, we have our guidelines, which kind of give us a roadmap as to how to manage the disease and really, it’s still very basic. We want to look at patients from the standpoint of their presenting features. There are risk models such as the so-called European long-term survival or ETLS model, using basic blood parameters really mostly can tell us about the relative risk of CML and how it might respond to therapy. Of course, we want to rule out advanced-stage disease and that’s one of the primary roles of a bone marrow study done at diagnosis, but careful clinical assessment and key molecular assessments, including a bone marrow, really helps us place patients properly for the next step which is to choose therapy.

And this probably presents a bit of a challenge because when you have a long list of good agents to use without as much direction, based on patient characteristics or disease characteristics, it becomes need for a long discussion. A new patient in clinic with CML choosing therapy could be a pretty expansive discussion when you have four drugs to discuss. But as you can see, the risk stratification helps — higher-risk patients probably should be directed more towards the second-generation agent given their ability to put patients into deeper remission faster and a somewhat higher protection against progression. Whereas patients with lower-risk disease, imatinib is still considered and this was the prototype drug in which we know the most about and where safety is the best, still considered a preferred option.

All of these options are good. The differences are small. And we’ll get to that in a moment. So this is again another good problem we have in this space.

Another important point to make, something that we need to pay attention to is that CML being a survivable disease in a population where there are often other health issues, is that the other health problems and the comorbidities present in the CML patient really matter.

So this is just some data showing the fact that patients with different Charlson Comorbidity Index measurement, but that would people in excellent health or people with multiple medical problems, heart disease, kidney disease, lung disease, etc, they have similar outcomes. It doesn’t impede your ability to get, as you see on the left, a cytogenetic or molecular remission. It doesn’t increase your chances of progression of disease if you have other illnesses. But unfortunately, those comorbidities still affect survival and age as well. So managing the patient of older age with comorbidities is entirely important because their CML outcome should be excellent. And we have to marry the agenda of internal medicine, taking care of the whole patient, with that of the hematologist. And one important area, for example, is cardiovascular risk assessment and cardiovascular health.

Again supporting this notion of how treatable and survival CML is, this is some of the key data from the original imatinib trial. And this is a 10-year report. If you look at this trial and didn’t know the background, you’d say well, it’s not much of a difference. So this is showing you the survivability of CML, in gold, the patients who received imatinib, and in green, the overwhelming majority of patients who briefly had interferon and then were crossed over to interferon and cytarabine. The numbers of patients who remained on interferon was very small. And for a small fraction of patients, interferon can be tolerated and can serve patients over long periods of time. But this really represents first- and second-line imatinib and the survivability of it because the crossover was the overwhelming majority in this trial due to the tolerability and improved efficacy seen with imatinib.

So we can see upwards 80- to 90% of patients in the original IRIS trial did very well with long-term data.

Imatinib was first FDA-approved and very quickly we recognized that it was very good, but it wasn’t perfect, and there was an unmet need for patients with some degree of resistance and intolerance. And quickly we saw two agents, dasatinib and nilotinib developed fairly similarly in time. And they were first approved as second-line therapy. But based on the fact that their outcomes were nearly as good in the second treatment line, as we saw with imatinib in the first line, they were quickly compared to imatinib. And this is the DASISION trial. So this looked at dasatinib versus imatinib and looked at the advantages of dasatinib. And you can see, for example, 5-year major molecular response rates are superior, 5-year deep molecular responses called MR_4.5, this is where BCR-ABL levels generally become undetectable.

This is the notion of deeper and faster remission, which can occur with second-generation agents. Where you see the least difference interestingly, is an overall and progression-free survival. So imatinib and dasatinib are both so good that there are advantages for dasatinib over imatinib, but it doesn’t play out much in the difference in overall survival or progression-free survival.

Very similar data is seen with nilotinib in a comparative trial versus imatinib in the ENESTnd trial. So again, highly statistically significant molecular remission, both deep and particularly the deepest remission in MR_4.5, but very subtle differences here. This was actually one of the only trials where 400 mg twice-daily nilotinib did show a bit of an improvement over survival compared to imatinib. And again, small, but real difference in protecting patients against progression.

So our second-generation agents are very good. They’re well tolerated, and they provide some advantages. But as you can see, imatinib remains in the mix and is a highly effective agent and not that far away from our second-generation agents.

This last see highlight would be the early molecular response is improved with the second-generation agents and that can move patients more quickly into the right level of response.

A bit later, and we saw comparative trials for bosutinib versus imatinib. And this was the second of a comparative trial. There was a previous trial, but the BFORE trial showed, and this is a bit earlier data, but it showed the advantages now of bosutinib over imatinib. Bosutinib was much like dasatinib and nilotinib, developed as a second- or third-line agent. Just shortly after nilotinib and dasatinib were approved, bosutinib was approved as a second-line agent. And this data here led to approve for bosutinib in the frontline. So I’ve built for you this story of we became to have four FDA-approved agents in the frontline for CML, with advantages, but high efficacy and good safety across the board. There are distinct side effect profiles for each of the second-generation agents, which colors the discussion of which drug might be suitable for which patient. And we’ll cover that a bit more as we go on.

So, this question about what is the standard treatment? Probably varies, depending on who you talk to and the patient risk a after, sort of a case-by-case analysis. And this data here looks at imatinib at various doses, including some interesting trials in the middle called the TIDEL1 and TIDELII trials where imatinib was used at a higher dose or quickly escalated. And you can see that you can probably use imatinib a little better if you use it at higher doses or adapt early based on patient’s response. And there again advantages for cytogenetic response.

Imatinib’s molecular responses are shown here, and this is from the primary data and the secondary data. I’ve shared with you that molecular responses are improved with dasatinib and nilotinib, but again, the higher dose of imatinib may approximate that.

And lastly, the overall survival differences are very small, if at any. So we’re really dealing with milestone responses rather than survival advantages. And that should again temper our discussion and really move us towards a risk-based approach to each patient and full discussion about treatment options, not to dismiss first drug approved imatinib which is now available as a generic, but to select the right patient for a second-generation agent in the frontline. And probably moreover, really to adjust therapy, maybe to escalate imatinib if you believe the TIDEL data, or switch therapies if patients miss milestones. Because really, the overall goal is to get patients to a deep remission the safest way possible and efficiently as possible.

So on that note, if we look at a bit of a table comparing the toxicity profile, we can see that the drugs are dosed slightly differently. There is more hematologic and non-hematologic toxicity, for example, more myelosuppression in some of the second-generation agents. More metabolic changes, for example, with nilotinib, with more liver enzyme, cholesterol and blood sugar disturbances and things of that nature.

There are class effects I would say, such as pancreas enzyme elevation, lipase elevation see with nilotinib and ponatinib.

But on the bottom, I’ve highlighted some of the key questions which are probably not so much emerging now, but they’re persistently on our minds, questions about heart disease, cardiopulmonary and cardiovascular disease, vascular occlusive disease. Some specific toxicities such pulmonary arterial hypertension, as well as question about some effects, over time, on renal function and glomerular infiltration rate. These are some of the really important questions we have for disease where chronic therapy is still considered the expectation, although a defined treatment duration is a goal, patients can achieve what’s called a treatment-free remission, and we’ll get to that in the end. But we have to assume patients may need to take this therapy for years; it’s a marathon, not a sprint. So raising the risk of these kinds of events or decline in organ function are really important considerations.

Again, our NCCN Guidelines help us in quite a simple way here, traffic light schema always helps us. So patients need to move along milestones of response in a prompt fashion. We look for early reductions in BCR-ABL transcripts to be below 10% by 3 months, that’s’ a one log drop by 3 to 6 months. That tells us the patient is well on their way to hopefully, a deeper remission and potentially a candidate for a defined treatment duration. That’s actually an opportunity to switch therapy early. And from there we look for cytogenetic levels of remission, transcript levels, that’s PCR talking about on the International Scale, below 10, below 1, below .1% with time. And then of course, onto deeper remission and perhaps candidacy for a treatment cessation.

One way to look at it might be this, and when talking to patients I try to explain it that patients may start at different points, relative to their PCR, but very quickly they should fall into a groove of milestones of response, much like a runner hitting their marks at different points in a race. And we’re looking for these milestones over time. It gets a bit murky as we get deep into the water, if this were an upside down iceberg, when we look at deeper levels of remission.

When we talk about detectable status, that really is defined as the limits of an assay. And we’ve actually stepped back when we define deep molecular remission and we know, for example, in the NCCN Guidelines, look for remission below .1% and consistently below that, rather than being undetectable or entirely MRD-negative.

CML is a very interesting disease. We have patients successfully able to stop treatment, despite the fact that they may have detectable BCR-ABL transcripts at very low levels. And that’s a new paradigm.

We’ve seen data, and as part of this large observational trial, that we have such good guidelines and we have such good testing, but we don’t always use our tools as much as we can. And this is the data set looking at patients, frequency of testing of cytogenetic response and molecular response by 12 months. And you can see that in the US and Europe there’s actually, unfortunately, a fraction of patients not tested for the first 12 months for cytogenetic response, which they clearly should be. And even at about 15-, 20% fraction of patients not being tested molecularly, this is probably representing some improvements we can have when it comes to making sure patients are hitting milestones via testing. And there was even a campaign in one of the advocacy groups, patients asking their doctors what is my PCR. So we can all remind ourselves to get those testing done.

Why is it so important? You hear some data from Sue Branford from the Adelaide Group on top showing what is the difference between a patient who has an early molecular response or not? And you can see the impact across multiple different later and important parameters of survival, progression-free survival, and deep molecular response. Vastly different if patients do or do not achieve early molecular response. Again, an opportunity for change. The difference between people who do or do not achieve a major molecular response, they have a greater likelihood of losing cytogenetic remission which is a sign of relapse.

And then some data that’s clarified over the years, what is the role of mutations in this disease? And you can see that in lymphoid blast crisis, or PH-positive AML, we have the most influence, the most likelihood to adjust therapy or think about a change. Whereas on the far right, chronic phase disease, we have more limited opportunity, but it’s still important to know about and to think about when you’re choosing an agent.

Our guidelines also give us all the tools we need when it comes to modeling and risk stratification and guidance with regard to testing. And on the bottom of this table, and this hasn’t changed, the go-to drug, if you will, depending on the mutation you might see, because certain TKIs, certain gaps and certain mutations which may be resistant. And one wouldn’t be expected to memorize this data.

And then the mutation of choice is listed last, the T315I, which leaves us with only selective options.

So the practical approach to a patient with resistance is really to look at the disease phase, of course, and the journey, the prior exposure. And mutations are important, particularly the T315I. And there may be some guidance in regard to what one might see, although it’s somewhat imprecise. Sometimes there’s multiple clones. There may be more than one mutation in the clone. There’s that phenomenon. And I think we’re seeing better incorporation of more next-generation and ultra-deep sequencing to understand the emergence of resistance.

And the of course, on the more practical side, if the patient needs to switch therapy, this comorbidity question and toxicity question really is important — are there any contraindications? And can we mitigate any of the risk, particularly the cardiovascular risk. Because we move to later lines of therapy that becomes more and more of an issue.

Resistance to TKIs is really fairly well described. And again, hasn’t become a bigger problem but is a persistent problem and it is mainly due to point mutations in the ATP binding pocket were BCR-ABL inhibitors work. There can be very bulky substitutions such as T315I, which sit right in the center of the binding pocket, which preclude most of the drugs from binding. There are other mutations which affect the confirmation of the kinase in the phosphorylation loop, what’s called a P-loop, or the activation loop, called the A-loop, and they do affect things differently.

As we get into some of the newer agents, I think we’ve figured out a way to perhaps move around this issue. But we do need to look still. It’s mainly a question for patients who have more overt signs of disease response loss, patients with advanced phase disease, patients with clear failure and patients who have hematologic and cytogenetic relapse. And this stands true for the ELN and the NCCN.

If you look at data though from this data set from a large analysis in Italy, how often is a mutation analysis going to yield you information? On the bottom, if you have a patient with a suboptimal response, perhaps a missed milestone at a more subtle level, not achieving cytogenetic or molecular response at a certain timepoint, the likelihood is fairly low. But on top you see where patients who have lost response, or who have some more of the early larger milestones missed, the yield is higher. So again, I’m not trying to deemphasize mutations, but just put them in their place and help us understand how to best use the testing.

I’m going to talk in a moment about better agents, and I’m not saying that our second-generation agents are not worthy in the second line, but they have some limitations. This is the data set looking at dasatinib, nilotinib and bosutinib at early and later time points showing how well they perform, mostly after imatinib. You can see that a majority of patients get the first step, a major cytogenetic response and roughly half get a cytogenetic remission. But there’s some differences in progression-free survival, and we clearly have some unmet needs here. So I’m glad to say we’ve seen other drugs developed and newer drugs beyond that.

The most important development was ponatinib, which I think in this slide we can see if someone had failed imatinib, failed a second-generation agent, what’s the likelihood of them getting a cytogenetic remission if they use another second-generation agent, or if they switch to ponatinib? And all of the data points towards ponatinib being superior. So we shouldn’t be saving ponatinib for the very last of our therapies, but we should be using it in a patient in whom we have that opportunity to salvage after a second-generation agent or other later lines of therapy.

The more lines of therapy a patient has had when we look at the primary ponatinib data, we see that the response diminishes, so we do want to use it, again when the opportunity arises and it’s appropriate, but earlier. And this holds true for both cytogenetic and molecular response. But we have to be cognizant of the fact that ponatinib does have some risks that are unique — they’re not unique to TKIs, but they’re somewhat higher frequency and in particular I’m talking about arterial occlusive events, which in the original data sets were much higher than we had seen with other TKIs.

It’s not a risk that increases over time, but probably in earlier risk. And probably our best solution to this is to properly risk-assess the patient and manage cardiovascular disease or risk factors that may be present and be very cognizant of these potential toxicities. But not to be afraid, that patients may need this therapy, particularly at the moment patients with a T315I mutation where the benefit is clearly outweighed by these risks still.

So let’s talk now about some of the newer and exciting agents. We have a good palette of drugs. I mentioned radotinib in the middle, and I won’t share any data on that. That is approved and available outside of the US and is probably closest to nilotinib. I’ll talk mostly about asciminib, which now represents what’s called a STAMP or specific targeted agent around the myristoyl pocket or a different location in the BCR-ABL altered protein that we see in CML cells.

We have very good Phase I data. We had a randomized trial which we believe will lead to FDA-approval and we have many other trials in development.

And then beyond radotinib, you see the three drugs I mentioned earlier, PFS-114, HQP1351 and K0706, or vodobatinib. These are drugs that are closest to ponatinib in structure and function, so they are able to overcome a T315I mutation, but they may offer different toxicity profile. And I think that’s an important advance if we’re able to see these drugs to fruition.

We were able to publish the Phase I data from asciminib now a bit ago and we learned a lot from this trial which, I think, was one of the largest and longest running Phase I trials I’ve been involved with — 300+ patients, 7+ years, multiple different arms. This is a good problem when you have a selective targeted agent without much in the way of maximally tolerated dose or dose-limiting toxicity. And you want to ask questions about the schedule, about combining it with conventional TKIs, because it has a unique mechanism of action, and you want to test it across all the phases of Philadelphia chromosome-positive leukemia.

How does this drug work differently? So we know all of these drugs are small molecule, oral agents, which inhibitor BCR-ABL. All the current inhibitors are utilizing the ATP binding pocket. Asciminib, or ABL001, binds at a different location called the myristoyl terminus, which is altered when BCR-ABL fusion happens which this cartoon is demonstrating. So as asciminib binds, it corrects the defect and allows for the confirmation change that would be present if BCR-ABL fusion hadn’t happened. This is the same thing that the ATP binding pocket drugs can do because they can deactivate and allow for more of a restored normal confirmation. So we have a different way of inhibition BCR-ABL in an area proximal to the ATP binding pocket which, again, allows us the potential for combination therapies and a completely different mechanism of action relative to anything to anything that’s going on at the ATP binding site.

So, the Phase I study, if we look at hematologic responses, cytogenetic response, and molecular responses, which, again, in a Phase I study was in the primary endpoint, is very encouraging. Overall, we saw, particularly in chronic phase in the first report, a very high response rate, including molecular responses. Probably one way to look at it would be by categorical shift, and I’ll get to that in a moment. But what the primary goal of the Phase I study was, of course, finding the dose and tolerability. And I think asciminib really represents a very safe, novel agent in this space.

We did see myelosuppression, which isn’t uncommon in a heavily pretreated population. And some, what I would say class effects, such as lipase increase, moderate degrees of hypertension, but no strong cardiovascular signal so far, at least in the Phase I trial. And nothing unique or new of concern. So really more disease-related vis-à-vis myelosuppression and some other things that aren’t unexpected.

I mentioned that some of the other details of the Phase I report showed that patients who were at different levels of remission were able to have categorical shifts, meaning patients in a cytogenetic response loss were able to regain cytogenetic response. Patients who were lacking molecular response were able to gain that. And the durability and resistance data from the Phase I trial is very encouraging.

People are probably most keen to hear about the T315I cohort because again, this is only currently treated by ponatinib and how did ABL001 perform in that group? So this was a subset of the patients in report. And you can see that hematologic response, either being preserved or brought on, and more importantly cytogenetic responses, were definitely observed in the T315I cohort. Very encouraging data. And molecular responses, which, of course, should be the next step along the way, as we follow this data further, we see both major and deep molecular responses occurring. Probably the discriminator most important would be what about patients who had or had not had ponatinib, can asciminib rescue a patient who had failed ponatinib? And the answer is, in some cases yes. Again, this is molecular response. So more basic response is even more so, and even here we see the ability to bring patients back into a safer level of remission, even after failing multiple lines of therapy, including ponatinib.

So asciminib really, I think, rose to the challenge of presenting a novel mechanism of action, ability as a single agent to work in patients with multidrug resistant CML who have failed several agents including ponatinib. And another point to make is that the dose interestingly was different for the T315I cohort versus other patients, which represents a bit of a unique feature of the drug.

The real test, of course, is a Phase III trial. So asciminib was put against bosutinib for patients with two TKI failure, if you will, they hadn’t responded well to two or more lines of therapy. This was not for T315I patients because this was a randomized trial, as it should have been, and bosutinib wouldn’t have worked in that setting. But the data was quite clear. The primary endpoint in the study was major molecular response at 24 weeks. We viewed major molecular responses one of the most important endpoints because major molecular response is viewed as a safe level of remission protecting patients against progression. And in this population, that would be important. And it was basically double with asciminib compared to bosutinib. So I think we were really encouraged by that.

Cumulative responses seem to be continuing as we follow with more time to be superior for asciminib over bosutinib.

And if we look at perhaps an earlier timepoint of cytogenetic complete remission at 24 weeks, the difference is quite similar.

We need more time, but I think we’re also very encouraged that it’s not about just getting those early responses, but also getting deep response which may put patients into an even safer category, maybe even allow them at some point to think about a defined treatment duration. And asciminib showing some signal here that it’s got that potential.

The side effect profile was, perhaps as one might have expected, we saw in the Phase I trial that asciminib had more myelosuppression, or myelosuppression as we see in later lines of therapy not much different than other agents. And you can see towards the left that asciminib had a somewhat higher fraction of thrombocytopenia and similar rates of neutropenia. But bosutinib probably predictably had more GI toxicity with diarrhea, nausea and transaminitis compared to asciminib. So I think many of this was expected but I think the trial data really was necessary to show the tolerability differences.

The most significant side effects are listed here. And again, a bit more myelosuppression for asciminib and a bit more of the liver enzyme elevations for bosutinib, as we probably would have expected.

So is there still a role for allografting in CML? I get this question quite a bit. And if I were to highlight the fact that patients who have transformed disease, if they can be restabilized with TKI therapy or other therapies, transplant is still the only way to go. We haven’t been able to crack this code of patients who are presenting in blast phase or progress to blast phase. There are probably other mechanisms of resistance. And we need to treat them like complicated AML and ALL, which is really what, biologically, they are.

For patients who have T315I mutation, I think at the moment we have concerns about longer-term use of ponatinib, although it can be done safely. And now we have other agents. We have asciminib, which I think I’ve shared some data with you, and a list of other drugs under development which may give us opportunity here. So we’re encouraged there.

And for patients with complicated disease with clonal evolution, toxicity, very little response, I think they may, case by case, be also considered for transplant. Whereas other groups who have more simple resistance that’s amenable to treatment with a second- or a third-line therapy, or patients who are older age, transplant may not really be a suitable — or a need for these patients. Whereas some of the other groups it really is.

We can’t have a talk about CML without mentioning treatment free remission which is in the label for nilotinib.

We’re really motivated to get trial data available for patients who had initiated nilotinib as their frontline therapy. Whereas historically, we had mostly data with imatinib and treatment free remission. But I think we’re very encouraged to say that this is probably an opportunity for patients with any of the TKIs, this is some of the data, on the top, some of the oldest and longest running data from the STIM trial which was imatinib-treated patients in a very careful way, who had their treatment stopped, the very first trial. And we can see how flat that curve is which is very encouraging. There is, of course, a very predicted fraction of patients who aren’t able to stay on treatment; they need to be retreated within the first 6 to 18 months, basically. But thereafter, treatment free remission seems quite durable.

And we have maturing data from larger data sets, such as the EURO-SKI trial, where we’re learning a little bit more about what is the optimal duration of treatment needed, and how do we best select patients for this.

We have guidelines, and this is from the NCCN, about how to conceptualize which patients are amenable to a treatment cessation. It shouldn’t be taken lightly. It should be patients who have all the right criteria, who can be carefully monitored and who are clearly in agreement for retreatment. But it’s certainly something to consider, to discuss with patients. I always say it’s a choice that they can make. It’s not a must, but it’s a tremendous and wonderful possibility and is becoming more of our standard.

So recently diagnosed CML patient in my practice, most of them would benefit from cardiovascular evaluation. Most of these patients are in their 50s, 60s, 70s, much like I am now. So I would want to have my cardiovascular checkup to know what potential side effects could be more or less of an issue, depending on the drug that was chosen and to keep my good health overall.

Initial studies should include a bone marrow, still. And obviously, we have a number of different requirements with regular lab testing and PCR testing. And again, there’s opportunity for early optimization. And we want to think about perhaps changing therapy at an early time point. We don’t necessarily need to repeat bone marrow studies, but we need to perform regular molecular analyses to understand if patients are hitting or missing their milestones and think about repeated cardiovascular evaluation if they need to.

The milestones again are very important, 3-month response is very important to get a patient on the right course initially. You don’t want to miss the opportunity to change for patients who we wait a bit and we’re looking for more of a 6- or 12-month response. And again deep molecular response and major molecular response should be achieved relatively early, and 18- to 24 months should be the timeframe.

The goal of treatment currently is to get patients into the opportunity to think about a treatment cessation with deep molecular remissions. There can be some plateau. There can be fluctuation, so we have to be patient. But treatment free remission is now considered a standard practice, both in the US and Europe, with the right condition and the right duration of treatment, in the right patient.

So we really have a tremendously treatable disease now. A functional cure is feasible. We have a generic form of imatinib. We have multiple TKIs still in development. We have five approved in the US. I think we’ll have a sixth one very soon.

We really have a lot of good tools to understand optimization. Early response, early change. Resistance mechanisms. Mutation analysis is still important. We have really very good options, very good parachutes if we need to grab them for second- and third-line therapy. Ponatinib is a very good drug and with careful balance of toxicity versus benefit, can still be used quite effectively. And we look forward to other options such as asciminib and other drugs in development.

And the war on cancer and the original TKI bullets, which were developed and approved now in 2001, 20 years later, we have an even better story to tell.

There’s actually an unmet need still. Well, maybe half of patients who are eligible to think about treatment cessation, half of them don’t and they may kind of feel like they’re in CML purgatory, if you will. And we have some trials in development and we have a nice group in the US called the CML Consortium, named after the late Jean Khoury, and I think we’re all working towards this unmet need for patients who many not be able to stop successfully the first time, maybe they can stop a second time.

Case: A woman in her early 40s who received imatinib for 20 years for chronic-phase (CP) CML

DR MAURO: We have woman, unfortunately diagnosed at a very young age, 23, who, of interest, was a clinical trial participant and went on imatinib with low-dose ara-C as her first therapy. But 20 years later she had imatinib with deep molecular remission. She was able to have three children, spaced out, where she stopped her therapy and with each pregnancy, she didn’t have much change in her deep molecular response. One might have thought that she was an excellent candidate to think about stopping treatment, and indeed I did.

Ironically, when she had stopped, not for pregnancy, but for the deliberate reason to see if she could stay off therapy, she needed retreatment. But she was able to regain response very quickly with imatinib at standard doses. She’s now awaiting some of these trial options I talked about, and we hope to enroll on a second treatment free remission trial where asciminib actually can be combined with imatinib.

She tolerates imatinib pretty well, although of course she’d love to be off it. But this is just, of course she’s been through a lot and had to put up with a lot, but she’s been able to live her life and grow her family and not have much in the way or morbidity or clearly anything worse from her CML, with good therapy. That’s just one example.

Case: A man in his mid-60s with CP CML and cardiovascular risk factors

DR MAURO: I bring this second case really just to share how toxicity can be a really important topic and sort of a sleeper.

Here’s a lovely patient of mine, a principal, this is the classic story, all was well. Was getting closer to retirement. And comes back from a cruise and his blood counts are abnormal. And he was put on nilotinib therapy and eventually made his way to my practice. And he had done really well. He was in a deep molecular remission. He had just mild side effects. I was concerned, he had some cardiovascular risk factors. I counseled him about that, and he was hesitant to switch. What I really didn’t want to have happen happened and he, unfortunately, developed what looked like unstable angina. Unfortunately, it was diagnosed and he underwent bypass surgery for what was then fairly severe coronary disease. And there wasn’t any way we couldn’t subtract that and say that nilotinib potentially might have exacerbated that. And since he was doing so well, we switched to imatinib. And he did continue to respond. He had a bit of a slowing of some of the depth of his remission, but he just initiated treatment free remission now, having been patient and waited for a bit longer time, based on some of the data supporting when is the right time to think about a stop in therapy.

So he was able to gain that deep remission rapidly with nilotinib. Unfortunately, he did have what could have been some exacerbation of underlying cardiovascular disease. Again, it’s probably impossible to know exactly. But we were able to safely switch him to imatinib and he still was able to take advantage of potentially a defined treatment duration and we hope he’s able to stay off therapy.

Case: A man in his early 50s with intermediate-risk CP CML 5 years undetectable on asciminib

DR MAURO: And then lastly, what about these newer agents? And sometimes things get pretty dire. This was an, again just a lovely gentleman. He’s a housepainter. Very simple, nuts and bolts kind of guy. CML, chronic phase, who we would have expected to have done well. He had intermediate-risk disease.

First had nilotinib therapy and really didn’t have much in the way of response. Developed some mutation, which may be resistant to nilotinib. Dasatinib was tried and could have worked against that mutation, but he’d actually progressed. So he’s moved on to ponatinib and achieved a molecular remission. His dose was reduced as per the label and again, I wouldn’t fault that. That’s exactly the way we’re supposed to manage it, but, unfortunately, he then had molecular relapse with yet a different mutation. And this probably speaks to some of the biologic instability of CML when it has some degree of primary resistance, and he now loses the cytogenic response despite re-escalating ponatinib.

So where would this gentleman be if we didn’t have other novel agents? He was a very early trial participant for the asciminib trial, and he went on it as first dose with stable disease, which is always a good sign. And then typical for a Phase I trial, we were able to escalate his dose. He’s now 5 years undetectable on asciminib. So now we have patients taking advantage of novel agents and we may even be able to think about could he have defined duration of treatment, even though he had resistant disease? And could he go into a treatment free remission?