Less-Intensive Therapies for Acute Myeloid Leukemia Tied to Higher Mortality Risks

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Aaron Gerds, an Associate Professor of Medicine and a Hematologist in Cleveland Clinic's Leukemia and Myeloid Disorders Program. He's here today to talk to us about the use of less intensive therapies for treating patients with acute myeloid leukemia. So, welcome Aaron.

Aaron Gerds, MD, MS: Well, thank you very much. It's a pleasure to be here, Dr. Shepard.

Dale Shepard, MD, PhD: Well, I appreciate you being here. So maybe to start, give us a little bit about your role at Cleveland Clinic. What do you do here?

Aaron Gerds, MD, MS: Yeah, so my main role is seeing and taking care of patients with leukemia and myeloid disorders, as the title of our group suggests. So, I have a particular interest in treating patients with myeloid neoplasia, particularly myelofibrosis and the myeloproliferative neoplasms. That's where I spend most of my time, but certainly my role extends into other diseases as well. Within our group, we treat acute leukemias, chronic leukemias, as well as some rare diseases too, that are hematologic in origin. So we see the breadth of hematologic issues within our group. The other 1/2 of my job is, I'm involved with clinical research. So I help develop some of the infrastructure for our cancer center, not only our Taussig Cancer Center, but also our comprehensive cancer center, which we're a part of in partnering with university hospitals and Case Western Reserve University.

Dale Shepard, MD, PhD: You're a busy guy.

Aaron Gerds, MD, MS: Yeah. It keeps me hopping.

Dale Shepard, MD, PhD: So, today we're going to talk about a topic with acute myeloid leukemias. And we're going to talk about less intensive therapies and some work that you had done with that and how less intensive therapies impact on mortality. So, I guess just as a backdrop, because we have a variety of people listening, what would be considered less intensive therapies? And we may talk about this a little bit later in terms of modern world and what that means, but for the purposes of this study, we're going to talk about, what does less intensive therapy mean?

Aaron Gerds, MD, MS: Well, for the longest time, we really had two bins of therapy, if you will, for acute myeloid leukemia. So younger, "fitter patients," you would consider intensive therapies. And everything that isn't intensive was considered less intensive. So it was a category by exclusion, if you will. So intensive therapies, we often think of seven plus three induction chemotherapy. So seven refers to seven days of continuous infusion of Cytarabine, and the three is three days of anthracycline, like doxorubicin. So, seven plus three has been around forever. So the first publication was in 1973. So we can think back to 1973, other things that happened was the founding of the CN tower. The foundation was put down. Pink Floyd's albums were very, very popular. Dark side of the moon, I think came out that year. And Nixon uttered, "I am not a crook."

So that just puts this in context, and we've been doing seven plus three for a very long time. And up until 2017, it was the standard for intensive therapies. And everything that wasn't seven plus induction was considered less intensive. And really for the longest time, it was low dose Cytarabine. So that same infusional Cytarabine when you give an intensive, just given in smaller doses once a month in continuous cycles. So then later on, azacitidine came along. Which had a comparable intensity. So less intensive therapies you can deliver as an outpatient. In fact, low dose cytarabine, patients give it to themselves at home even.

The chemotherapy they've given it to them. They do their subcutaneous shots twice a day for 10 days, once a month. Azacitidine is generally given over a week a month. But all outpatient therapies where intensive care is the nuclear option, right? We put people in the hospital, they get this intense chemo, they're there for a month, we blast all their bone marrow, not just the leukemia cells, but their whole counts go down. And that, as you would imagine, it comes with risks of increased side effects and complications. Potentially increased mortality. Where less intensive therapies, those risks are perceivably less. And really the debate that's been ongoing, particularly in patients who are older, say over the age of 65, which is the better approach?

Do you take the thing that is more intensive, more likely to lead remission, but has a higher complication rate? Or do you do something that's a little gentler that maybe not hits the numbers of remissions, but is also less likely to run into a significant complication in terms of morbidity and mortality?

Dale Shepard, MD, PhD: So when we think about mortality in the setting of this trial and really just big picture, and you've alluded to this, mortality can be something bad from the treatment itself and mortality can be, I didn't effectively treat the disease and then a patient dies of their disease. So, how do you balance that? How do you think that through?

Aaron Gerds, MD, MS: I think that, that's ultimate problem with all this, right? So we try to come up with surrogate markers. A lot of different cancers will have surrogate markers for the overall point of the whole thing, is to have people live longer, right? So, in leukemia we use complete remission, meaning that the bone marrow is morphologically free from leukemia. We don't see it under our microscope, and also the patient's blood counts return to normal. So complete remission has been the quote unquote gold standard as a surrogate for overall survival. And this hearkens back to the days of intensive therapy, where if people got into remission, they live longer, if they didn't get into a remission.

The problem is, with these less intensive therapies, sometimes is unclear if a remission is truly a surrogate for overall survival. Because you do have these trade offs, as you mentioned, between toxicity and improved response rates in terms of remission rates. And so really we try to lean heavily on randomized trials in order to understand, is this really making people's lives better? Because you can give all the chemotherapy in the world, you can get all the remissions in the world, but if a person at the end of the day doesn't live longer, then you're not achieving that particular goal. And that's not withstanding the whole complication of quality of life too, which is also very important as a patient age increases.

Dale Shepard, MD, PhD: And I guess when we think about that remission as a standard for a success, I guess over time you get additional therapies. And so, once a patient has had their failure of their initial therapy, what does the world look like now, in terms of our ability to salvage that patient? That didn't exist when those original trials may have taken place?

Aaron Gerds, MD, MS: Yeah. So again, 1973, we think about seven plus three coming out, later on we had Vidaza. And not a lot happened in acute leukemia, acute myelo leukemia, until 2017. So in 2017, midostaurin was approved. So it was a foot, basically a FLT3 inhibitor. It hits other things like key and other molecules as a dirty, tyrosine kinase inhibitor, but really it was a FLT3 inhibitor. And that was added on induction. And then after that we've had a series of new approvals. There's been CPX-351, also known as Vixios, which is a liposomal version of seven plus three that better tolerated in older patients. And there's been targeted therapies such as IDH1 and IDH2 inhibitors, there's other FLT3 inhibitors that have been approved.

So there's been a series of other drugs improved mostly in that relapse refractory setting, altering the course of these patients' diseases. Similarly, there's been additional data coming out that other lines of intensive therapies given if a patient doesn't get into that initial remission, can also improve survival. So that really complicates the picture. And then we haven't even mentioned transplantation, which is for many patients, the only thing that could potentially cure their acute leukemia. Which is a whole nother bag of toxicities associated with the treatment, but also potential benefit in terms of long lasting, durable, remissions.

Dale Shepard, MD, PhD: As a simple, solid tumor guy, I'm happy to hear about flip three therapies because I guess I got to say it was a little maddening as a fellow, knowing all the chromosomal abnormalities, and then ultimately coming to decision that we probably should give seven plus three.

Aaron Gerds, MD, MS: Yeah. The nihilist in me still says that, right? So, we talk about, yeah, FLT3 inhibitors, which are great. And we think about these things early on, but everyone's really excited about the IDH1 and IDH2 inhibitors, but it's a small part of the population, right? So, we're talking five, 10, maybe 15 down of patients, depending on what study you're looking at. So it's still a small fraction and you get these genomic reports, right? We do these multi-gene panels and you get back these gigantic reports and you're like, "Well, you can't target nothing here. Well, can't target nothing here." So it is still incredibly frustrating to get these reports and not have something you can go after.

Dale Shepard, MD, PhD: All right. So, great backdrop. Let's talk a little bit. There was a long term study that looked at this question about mortality related to less intensive therapy. So, tell me a little bit about what the study was and what the aim was at the start.

Aaron Gerds, MD, MS: So this study was actually a really big effort, across a number of centers, including Cleveland Clinic. Where we all partnered together to do this big prospective cohort study. So ultimately we also included a large retrospective cohort as well. So there was a time point where you looked backwards and we looked forwards. The backwards was your standard AML group. We gathered a whole large group of patients and got the typical outcomes. Age, comorbidities, blood counts, treatments. The key with the prospective cohort was we were able to gather additional data, quality of life data. And interestingly, we also collected a perspective data. So the patient's perspective of the intensity treatment, the patient's perspective of chances of cure, as well as the treating physicians perspective on these things. To me, that is the most interesting part of this study.

Not only were we able to look at our typical outcomes, remissions, survival, all those types of things, but what it would people really expect to achieve with this therapy? So to me, that's the really interesting part. But this is a huge database. 2000 patients were included in this analysis, both the retrospective and prospective part. So, a really big group of patients follow for 11 years. So a long term outcomes as well. And really the take home points, center around this whole concept we have of older patients. And I gingerly say this term, because I know some people are offended when you use this word, and I don't mean to be ageist, but clearly it is more challenging as an older patient gets to deliver intensive therapy. And when patients get over the age of 65, there's a debate of what we should do.

There are some in this debate that firmly say, "We need to do non-intensive therapies." They should be getting Vidaza or azacitidine. They should be getting maybe azacitidine with combination with an inhibitor of some variety, and not doing induction. But our data from this long term experience showed that survival was actually better in older patients who got induction chemotherapy. And the take home point there is if you have a patient in front of you who has acute myelo leukemia, new diagnosis of acute myelo leukemia, and they're a relatively fit person, say they are 70, but they don't really have much of the other. They don't have liver disease or the kidneys are still there and intact. And they go for a bike ride twice a week and a pretty fit folk, there is to be an advantage for induction chemotherapy in those patients.

And this is based on a prospective cohort observational cohort. Now, that's going to be fraught with bias, right? Because we're going to eyeball these patients and they pass the eyeball test for this, we're going to do that, as opposed to doing less intensive therapy, this is not a randomized study. But, with this prospective cohort, it does suggest that patients who you think can undergo this, that there is a survival advantage there. And that is contrary to what some of the common wisdom is right now in the leukemia world. Certainly there is a faction who think that we should never offer anyone over the age of 65 intensive chemotherapy, the seven plus three. But there seems to be a role for this.

Dale Shepard, MD, PhD: It's an exceedingly random question, why 65?

Aaron Gerds, MD, MS: It's arbitrary. Well, it's one of these things that it starts and you can't stop it. Right? So, older analysis done, 20 years ago, 30 years ago, used this as an age cutoff for between younger patients and older patients. And it's just stuck with us forever. And not just an acute myelo leukemia that we see this age pop up in transplant studies. It's just something that's persisted within the leukemia world as an age cutoff. There have been other analyses that have tried to find a better age cutoff and maybe suggest 60, there's some sort of inflection point there, others have suggested 70. So I guess it ends up being the average anyways, but yeah, it is a purely arbitrary number.

Dale Shepard, MD, PhD: And I know in the field of geriatric oncology, there's been a lot of effort into, and really most effort has gone into picking patients that might be able to tolerate chemotherapy for instance, and really, probably not enough in terms of once you decide to treat, what do you do about it? Are there similar tools that are used in the he malignancies?

Aaron Gerds, MD, MS: There're quite a few. So one of our collaborators in this study developed something called the transplant-comorbidity index, Mohamed Sorror. And that's been used for a very long time to understand what an individual's risk is undergoing transplantation of having a complication from the transplantation. So, you look basically at all the patient's comorbidities, liver function, kidney function, lung function, all these types of things and their histories. And you can come out with a risk. That's been applied to leukemia patients getting intensive therapies and it holds true. You can add in a few other factors like chromosomes in the aggressiveness of the disease and even come up with a more comprehensive prognostic indicator in trying to understand who should get intensive therapy and who should not, by adding in not only patient related factors, but disease related factors.

In fact, the same collaborative group that published this paper, we published this comprehensive leukemia risk stratification earlier. That was a publication in JAMA Oncology, a few years ago. But in this analysis, it seemed to be that the fitter a patient was, but also the higher risk of their disease, they also benefited more from those induction chemotherapy. And this held true in patients, not only over the age of 65, but over the age of 70, even. So by looking at core comorbidities specifically, we were able to identify a group of patients that did benefit from induction chemotherapy versus less intensive therapies.

Dale Shepard, MD, PhD: And so AML tends to be a disease where people roll in, they're really sick and you have to make some relatively fast decisions on treatment. So, you mentioned chromosomal analysis. Are there any other biomarkers or any other tests that might be able to predict who really should get less intensive therapy?

Aaron Gerds, MD, MS: Yeah, there aren't any quick turnarounds on that, unfortunately. At the end of the day, what steers us towards doing intensive therapy versus less intensive therapy is the good old fashion eyeball test. You walk on the room, you look at the patient and you're like, "Yeah, you should not get induction chemotherapy." Or you walk in the room and you're like, "You know what? I don't think this is a terrible idea." And that overall is what we do. It seems silly, antiquated and completely subjective. And it is. But, there isn't a better predictor beyond the eyeball test. We make these fancy models and we do all these things because we like to do publications and we got to do something, right? But at the end of the day, it's always the eyeball test. In terms of genomic markers, we do get things turned around quickly in some instances, which can change treatment.

So the example would be FLT3 analysis. So we can get that back in less than 24 hours. And that will help us determine if a patient is getting induction. Should we add midostaurin on top? Because if a FLT3 mutation is present, which is present about a 1/4 of patients, newly dealt with newly diagnosed AML, we can then add the FLT3 inhibitor onto their treatment, within to under their induction treatment. The other one would be if they're one of those rare APL, or acute pro myelo acidic leukemia patients, we can get that answer back quickly within 24 hours using a FISH or PCR test and switch and not do induction chemotherapy, but rather do ATRA and arsenic therapy.

The last one that we try to get turned around quickly is this small group of patients called core binding factor AML. So this is in version 16, translocation H21. And patients with those translocations, you would add gemtuzumab ozogamicin onto their seven plus three induction. And that we can also get by FISH testing turned around pretty quickly. So those would be the instances where genomics would change, but it doesn't tell you the difference between induction or intensive therapies and less intensive therapies. It's only things that we might add on to the intensive therapies to make them work better.

Dale Shepard, MD, PhD: Got you. Now, interesting you mentioned about in this study patient perspectives, physician perspectives, anything that particularly stands out as something that we should know about.

Aaron Gerds, MD, MS: Yeah. So, it's interesting and we haven't really sifted through this data in large amounts yet, but there's a couple of themes. There is a discordance between what patients think and expect versus what their treating physician. Because this is pair too, right? It was their doc and the patient. There's a discordance between what a patient expects and what a physician expects. And a patient's appreciation of how curable their disease is often higher than what the doc might be thinking. But also if you look at the doc's impressions, it's often not concordant either with what published data is. So if the chromosomes and cytogenetics are available at roughly after the time of diagnosis, we were filling out these surveys roughly two weeks after the patient was admitted.

So, we did have the cytogenetic data back then in most instances, and you get someone with a complex carrier type, which sounds bad and it is. And docs would say the chance of cure with chemotherapy might be 50-50. And you're like, "Yeah, that's probably not true based on what we know about chromosomal abnormalities."

Dale Shepard, MD, PhD: Now, out of curiosity, how patients certainly walk away with higher expectations, they often think they'll be the 1%, and it makes good sense. I get that. How often do patients either come into clinic after you've gathered all of this and ask again about prognosis, or how do you approach once you have the bigger picture? Because a lot of these discussions are happening real-time and you may not have that. What does that look like?

Aaron Gerds, MD, MS: Oddly enough, it doesn't seem to come up much after the initial shock and awe, if you will. And I think that's something that unique to acute leukemia. So, if a patient goes the induction route, so they get in the hospital, you walk in one day and say, "Okay, you have acute myelo leukemia and we need to think about treatment." And you actually launch into treatment, before you get all this genomic and chromosomal information back. Genetic analysis takes 10-ish business days to come back. Chromosomes right now are coming in about two weeks. Some centers, you can get them back in a week. Right now we're averaging around two weeks, due to shortage is in our lab in terms of manpower, but you've already launched on induction chemotherapy at that point. So circling around the expectations is very difficult. And when this information comes back, it's usually a second conversation.

Okay, we already did this. The cow is out of the barn, but here's now what we expect going forward, right? And for most patients though, you're framing that around the next step. So, I use the analogy of a board game. So, most of us have played shoots and ladders or Candyland, stuff like this. Where everyone starts at the same spot on the board. And there may be different paths to the finish, right? You might go through high dose RSE consolidation. You might have to go through transplantation to get to that finish, which is a cure.

And the genomic information and chromosome information really tells us which path we should be taking for steps two, three or four. The first step's always the same. We got to get someone in remission. So, we do the induction chemo. That hasn't changed since 1973, in large part. But it's more of trying to reframe that conversation like, okay, we expect a decent chance of remission with this initial treatment, but in order to keep this away forever, we might have to do something differently down the road for steps two, three, or four.

And then that's how I tend to frame these conversations. In patients getting less intensive therapy, you usually do have all this back, because there's time. You got time to get the genomic information back to plan the strategy out a little bit better and have those ongoing conversations. So the way you strategize how to have these discussions, definitely difference between intensive and less intensive therapies.

Dale Shepard, MD, PhD: What are the gaps?

Aaron Gerds, MD, MS: There are lots of gaps. The fact that I've mentioned now 1973 for I think the fourth time means we need better therapies, really that's it at the end of the day. The treatments we have are great. And there have been a ton of advancements. Again, IDH inhibitors, FLT3 inhibitors, liposomal seven plus three. It's all been steps moving forward, but it's still short. I also mentioned the annoyance of getting a genomic report and having nothing to target in it. So, really thinking about different ways to target or get these diseases. I've also mentioned that there's a big push for triple therapies where we are taking, say a azacitidine backbone, added in medications like a IDH inhibitor, plus maybe a BCL2 inhibitor, and putting it all together in this new multi-drug package. The problem with a lot of these multi-drug packages, they're incredibly toxic, right?

You see severe adverse events ranging upwards of 60, 65% grade three, grade fours. Which is really, really high for someone getting potentially non-curative therapy. And so we need more targeted therapies, therapies that are less toxic and really the future too, I think is lastly trying and harness the immune system. CAR-T cells, cellular therapies are all the rage. They are certainly the bell of the ball right now. I like to say that transplant was the original cellular therapy. It's been around for a long, long time and it works right. It can cure these patients. But we need to make a better mouse trap. And I think cellular therapies are going to be the next thing where we can potentially cure these diseases, agnostic of mutations, and lead that long term outcomes, that are really positive.

Dale Shepard, MD, PhD: Very good. Well, I appreciate all your insights today and thanks for being with us.

Aaron Gerds, MD, MS: It's been my pleasure. Thank you.

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