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Maxim Jacobs
28 March 2017

Edison KOL call

Edison KOL Call: AML

The fifth in our KOL series, Edison sponsors an interview with Dr. Douglas Smith of the Johns Hopkins University School of Medicine.  The conversation featured a discussion on emerging AML treatment.

Call Leader: Great. Thank you so much for joining us Dr. Smith. I was wondering if you could just start by describing your practice?
Doctor: Yes, I’m at an academic medical center. We have a leukemia program within the academic center, so we have a fairly large volume of leukemia patients. My research interests are in drug development and novel therapeutics so that’s where I spend most of my research time. I’m one of the senior folks in our program having been here for 22 or so years in this leukemia world.

Call Leader: Great. I was wondering if you could walk us through ... What’s the usual course of therapy when you get a patient with AML into your practice?
Doctor: Yeah, sure. The approach to really diagnose patients with AML is to, number one, determine whether or not they’re a candidate for intensive therapy versus less intensive therapy mostly based on their medical comorbidities and age. Number two, we determine the prognosis associated with the type leukemia that they have.
Doctor: We use the markers of leukemia. Molecular markers, surface markers, cytogenetic markers to ... and the patient’s history of course, to try to determine the likelihood of whether that leukemia’s ... would respond to traditional approaches with infusional chemotherapy. So those are the two big things that we do when people first arrive. The majority of our patients are treated with ARC plus an anthracycline combination, so sort of a standard approach.
We’re lucky that we’ve had clinical trials for people that are newly diagnosed or recently relapsed or refractory so, putting patients on a clinical trial is a very high likelihood in our institution and it’s something that we do a lot of. But our standard approach would be an ARC-based, plus anthracycline chemotherapy.
Call Leader: What percentage of your patients end up going on clinical trials?
Doctor: Probably close to 80% of our patients our treated on a clinical trial. Most of those clinical trials are therapeutic. Some of them are donation of blood and bone marrow and those types of things but for the most part the majority of our patients are put on clinical trials.
Call Leader: Okay, great. Do you see that changing any in the next few years? I’m probably skipping ahead a little bit, but just with ... I mean, Vyxeos is going to be coming online, Venetoclax probably, it can be used off-label now and will be on-label in a few years, and then you have Midostaurin from Novartis and the Agios IDH inhibitors. You might have a lot more on the market. Will that take away from the clinical trials that are still ongoing?
Doctor: Well, my hope is that we’ll still have clinical trials looking at other drugs, and that we will continually refine the approach. So just like I said in a very big global we look at somebody who’s old and frail and say, “You’re not a good candidate,” or somebody who’s young and robust and say, “You are a good candidate for the therapy.”
In addition, moving forward when we have these other drugs to play with, I think we’ll be able to say, “Okay, your molecular markers show you have an IDH1 mutation. You’re going to get chemo plus an IDH1 inhibitor because it’s available off the shelf, it’s approved, and we can use it.” Many of those patients will get that as their standard of care and the people that don’t have an identifiable marker or whatever, those people would still be potentially eligible for clinical trials moving forward, with new agents and new targets, etc.
It may become more personalized sooner than many people would have thought of.
Call Leader: Okay great. Which subgroups within AML would you say are underserved by current practice?
Doctor: I always hate the word “most” but there’s no really great group where things work that well for. The exception being patients with APL where we’re likely to cure the majority of those patients and we can get away without using lots of cytotoxic chemotherapy. It’s not that the treatment isn’t hard, but it’s a lot different than with cytotoxic chemotherapy.
Outside of that, I think every way you want to slice it to me I think that we can probably do better. We always talk about the holy grail of drug development as elderly leukemia. A low-toxicity drug but with high efficacy, it can be taken by pill and those types of things are sort of ... always been the challenge in drug development, can we find these drugs where we can treat older patients noting the median age is pushing 70 for patients newly diagnosed with AML, so I think that group is the one we all talk about but I think that a young healthy person even with a favorable cytogenetics, with a 40-plus percent chance of relapsing over the course of their lifetime, I think that group’s underserved as well.
Even if you think they’re going to do pretty well, there’s most people with leukemia in the end don’t get cured, have to go through intensive cytotoxic chemotherapy, and it’s a challenge, so I think we can do probably better in all the groups that we talk about.
Call Leader: Okay, great. Now, why has AML just always been so difficult? I feel like there’s always dozens of pipeline candidates that are trying and then generally until recently most of them fail.
Doctor: If you were on the east coast, I’d invite you the Grand Rounds on Friday. I’m actually doing a talk on this, if you can believe it or not, talk about the serendipity of a call.
We don’t really know the answer. I think the biggest drug development problem in leukemia is that the FDA has wanted survival data, and survival data are challenging in AML, because there’s other treatments that we can use and sometimes people get salvaged with a cure like a bone marrow transplant, so when we look at salvage options for folks, it tends to mitigate some of the data from response, so even though most of the people that have refractory leukemia will die with their leukemia and die relatively quickly, one of the challenges we’ve had is showing a survival advantage of a novel agent.
The second challenge is that all meaningful therapies to date for AML have included multiple drugs, so it turns out that it’s hard for the FDA to approve a drug, a novel drug, when it’s in combination because they always make the argument, “Well, we don’t know how much of the success of this combination is due to the novel drug.”
Again, leukemia is a multi-mutation, multi-stem cell, multi-clonal problem and so it’s hard to show that you can ... a single drug can have a big impact, on its own, and it’s hard to show survival, because when people don’t do well, there are other things that we try that helps sustain them and makes so that the survival advantage is hard to assess in a lot of our trials.
Call Leader: Okay, that makes a lot of sense. Now, when you’re assessing something like survival, is there a hazard ratio that you have in your head that you think, “Okay, this is the delta I need to see.”
Doctor: It depends on the group, so the answer is no. I think the common language that’s thrown around by my colleagues and myself when we’re talking with companies or developing trials is, when you’ve got a predictive response rate of 20-30%, you’re going to want to move that up to 40-50%. You’re going to want to almost double that if you’re looking at a response rate where you can look and say, “In this small study the response rate was 45%. We definitely need to look into this drug more,” versus a response rate of 33%, which is marginal at best and you say, “Hey, that’s not such a good benefit. Maybe this drug isn’t such a great drug.”
When you’re looking at response rates of 50 or 60%, then for example if you use induction chemotherapy and you expect 60-70% of people to get a remission, and you say, “I want to add a FLT3 inhibitor, in IDH1 inhibitor, to that regimen, I want to make it better,” I think in that situation, where we’re probably not trying to make it a 90% CR rate. We’d like that, but I think we’re really looking at, can we make a more meaningful CR so that people survive longer or have leukemia-free survival, relapse-free survival, in that circumstance. It’s slightly different depending on the patient population that we were thinking about.
Call Leader: Okay, that’s very helpful. Just going to ... getting your thoughts on some of these individual drugs. In terms of Vyxeos, the improved 7 plus 3 regimen, how will that change practice?
Doctor: I’m waiting to see. My bias is that I think this is a step forward and I think my hangup is that it’s an expensive step forward, so in the end I worry that science and clinical trials outcomes will only play a minor role in deciding what happens with this drug, and insurance companies and third party payers and P&T committees will make it more of a challenge. I think that’s a real legitimate worry when we talk about expensive therapies.
Even ones that seem to show a benefit that we’ve been ... We’re a desperate community looking to approve a drug in this space, and it’s probably the one. A lot of people think it’s likely to move forward so I think in our practice I’m hoping that my colleagues and I will all agree in a population, secondary leukemias for example, older patients, that this will be our standard of care. I think we’ll develop an algorithm to try to do that.
I think the next step in our job and what we really should be doing then is looking at, are there other groups that might benefit from this drug? Should we look at younger people with the same type of secondary leukemias, then younger people with more standard leukemias? Our job is to really assess what are we missing, what else can we offer? How can we do this so that it benefits more and more patients.
So I do think that ... my hope would be that if it’s an effective drug for other populations, that its indications will eventually expand over time. But we have to do those studies. I don’t necessarily think your P&T committee’s going to let you give a really expensive drug in a situation where it’s not been proven to be better than the standard drugs you can pull off the shelf.
Call Leader: Okay, so, just to expand on that a little bit, are you now pretty limited in terms of your ability to use off-label drugs, especially if they’re branded and expensive?
Doctor: Yeah, we are. Certainly, big centers don’t want to absorb the cost of an insurance company that’s not going to pay for a drug. We’re limited if an insurance company comes back and says, “We’re not going to pay for that because it’s not an indicated therapy for that problem.” So our P&T committee would restrict us the availability of that to the indications for super expensive drugs. That does happen.
Call Leader: Have insurance companies gotten much more difficult with regards to off-label usage in the last few years?
Doctor: Yep. I think they’ve become more sophisticated and ... The answer is yes.
Call Leader: So, just extrapolating the Vyxeos data from secondary AML with the primary AML, even that might be too big of a jump for them?
Doctor: My answer would be yes. I think it will be a challenge to substitute a very expensive agent for a ... expensive but not as expensive treatment. My guess is that they will not want to do that outside of the context of a clinical trial or not without clinical trial as data.
Call Leader: Okay. How expensive is it to treat a moderate AML patient, just generally? I know for standard 7 plus 3 therapies they need to be in the hospital for a long time, so it gets kind of expensive. How much of the total expense is from the drug?
Doctor:  Relatively small, but I think the ... I don’t know what the Vyxeos drug will come out as, cost wise, but it can’t be cheap, so I think it will contribute a significant amount to the hospital stay. Again, there’s sort of ... we compartmentalize these things but, insurance company will pay for your bed in the hospital and a different part of your insurance pays for your drug, and different part of your insurance might pay for your CAT scans, so there is an important component of how your insurance company pays for this stuff that will be important.
Call Leader:  Okay, great. That was helpful. What do you think at least theoretically, is there any reason why Vyxeos wouldn’t work in a primary AML population?
Doctor: No. Absolutely not. There’s no obvious reason why it would or wouldn’t work. People that study this for a long time say, “Why does it work at all?” Nobody really knows. I would agree with your supposition that there’s no reason to think it wouldn’t, but whether it’s better or not we just don’t know.
Call Leader: Is there any toxicity concerns with Vyxeos compared to 7 plus 3 that you have?
Doctor: The answer is not really. Obviously any studies that are done with this moving forward will certainly look at the death rate from infections, and the red flags that people may have seen with the studies that have been done, but for the most part I don’t think ... that there’s nothing that really stands out that I would expect in a younger healthier population to cause trouble right off the bat.
Call Leader: Okay, great. Now moving on, what do you think about Venetoclax in AML?
Doctor:  Well, I’m a big fan of Venetoclax in AML. What I would tell you is that I think everybody ... a lot of us have been impressed with the clinical outcomes data in tough to treat populations.
Now again, I’m specifically referring to the combinations of Venetoclax, both either low-dose chemo, ARC, or demethylating drug. But the early data that have been presented at meetings so far suggests that there’s a pretty interesting response rate. Again, toxicity profile, there’s work to be done to sort out if the safety profile of it, but I think that this feels like a drug that’s contributing ... There’s been a ton of small studies. Just look at demethylating agents, there’s been a ton of small studies looking at other epigenetic modifiers to throw in there with azacytidine or decitabine for example, and all of these in small studies show they look pretty good combos, and in big studies they kind of pan out a little bit.
This looks good in the early studies, so you never really know when you do the huge big deal cooperative group study. There are data coming forth, I suspect we’ll hear about it at ASH this year. There are big data coming forward that suggest that we’re going to learn more about in a bigger study, a randomized study what kind of benefit we’re getting but the benefit that we’ve seen in the published reports so far with the combination suggests that it’s ... the responses are very interesting and very provocative.
Call Leader: Great. So, just assuming that the bigger studies end up being consistent with the earlier smaller studies, where do you see using Venetoclax within the treatment paradigm?
Doctor: I mean, I think that where we’re ... Elderly patients, AML patients you’re going to give a DNA methyltransferase drug a hypomethylator to is, you sort of say to yourself, “Why not use the hypomethylating drug in combination with Venetoclax?” So, probably get a better response rate, maybe a more durable response. Those things are very provocative so for sure in our mind, I would broaden it to say that ... I know that they’re looking at other populations like high-risk MDF and other populations like that.
I would say, “Jeez, I’d want to put this almost any time I was using a demethylating drug, I might want to try and see if I can get more bang for my buck with a drug like Venetoclax blocking the anti-apoptotic hit.” So, again it would be what will my insurance company let me do, and what will the patient do, but I think those are types of places where we would want to be using a drug like Venetoclax in combination.

Call Leader: Great. Is there any particular toxicities of Venetoclax that you are worried about?
Doctor: Again, I haven’t been. The company is very diligent and watching very carefully that we don’t see Tumor Lysis, or where people know how to manage it. That has been well-described as a concern. I think that prescribers of the drug will need to be thoughtful and educated about it, so I would only mention that as to say that is one of the things that people talk about and the company’s been diligent about making such people understand.
Call Leader: Okay great. Now just moving onto Midostaurin from Novartis, they showed a survival advantage in FLT3 mutated patients. What do you think about that one? The median survival, I thought there was a big delta, but because the curves were flattening out and the hazard ratio was only a 0.77.
Doctor: We’ve done a lot of FLT3 work here through the years so we know a lot of the FLT3 targeted agents, so they’ve been of great interest for the lab researchers here in Baltimore. The truth is that this is a very interesting ... We’ve waited a long time for a drug to show that it’s improving things.
Our institutional bias is that a FLT3 inhibitor is really changing the way FLT3 leukemia outcomes happened and successful induction, a bone marrow transplant and a FLT3 inhibitor, that combination may really move this into, from a really incurable, tough to cure form of leukemia, into a moderate or even better more easily cured form of AML. So, we think that having a FLT3 inhibitor and applying it to patients during their primary therapy and then as a maintenance strategy following transplant, makes a lot of sense and I think that is a step forward in the FLT3 space.
Call Leader: Great. What percentage of your patients would you say are FLT3?
Doctor: We probably have a disproportionately high, a few percentage points higher just because we see a lot of FLT3, but I think we’re probably in that 20-30%, 20-25% of patients will have a mutation.
The criticism of the presentation with the Midostaurin was that the drug seemed to be equally effective in the patients with high allelic ratio FLT3 versus low, and the suggestion has always been that the high allelic ratios do the worse, and why would it be equally effective in a low allelic ratio scenario where the FLT3 may not be playing a role.
So one of the really interesting questions that’s out there that we wrestle with is, “Is this a general effect of the drug or it is really a FLT3 specific effect of the drug?” I’m not sure we all know the answer to that fully yet and I think that that’s one of the reasons there’ll be probably more studies, the FLT3 agents that will, I think, mirror the studies that have been done and a real effort will be to move even more effective single-agent FLT3 inhibitors into that space.
Call Leader: Okay great. Just moving on to the IDH inhibitors. What do you think about the Agios and Celgene products?

Doctor: I was never quite as enamored with the responses that early people, and that’s just as a personal bias. I looked at the data and for those drugs, IDH1 and 2 inhibitors, I was looking at the glass as partially empty, not that it’s partially full. I wasn’t jumping like crazy when other people were. I think the response rates have come a little closer to Earth than they were early on. I think that there’s cool stories that get us all excited about someone near death and then revived back to life and having six months playing golf. Those are exciting and fun so you realize that the drug has some activity for sure.
I think its utility may end up being in strategies like in combinations where it’s being studied now, again with this idea of a people you’re going to give 7 and 3 to, and they got a mutation, you give them the drug. Somebody you’re going to give azacytidine to, they have an IDH mutation, why not do the combination of the drug. So there may be ways, again, just to begin to peel off people and really individualize our treatments differently, I think they’re good drugs, don’t get me wrong. I just thought they were really good drugs, not super-duper life changing fixing everything type drugs, which they sort of had a little buzz about them early on, that they were these incredible compounds.
The coolest part is that it’s another mechanism that we can begin to exploit to try to make better therapies, because combinations, better so-called cocktails, and that’s the part that I’ve found very interesting.
Call Leader: The way you’d probably use them is in combination with what you would give already to the patient? You wouldn’t necessarily switch out something else?
Doctor: I think you can use them as single agents where you ... they have activity for sure but I think where they’re probably going to make the biggest impact long term is by using these drugs in combination with some chemotherapy based regimen. That’d be the first thing.
If we can prove that then we can say, “Maybe let’s just give an 80 year old a FLT3 positive leukemia.” Maybe an IDH1 inhibitor plus a FLT3 inhibitor would make it so you wouldn’t have to give that patient chemo. I’m making up little scenarios but you could begin to envision where people have a couple of different mutations and you give them a ... we’ll call it a cocktail, literally where you have, you pull the bourbon from here, you pull the ginger ale from there and you make a drink. You could pull an IDH1 inhibitor, plus a FLT3 inhibitor, or an IDH1 inhibitor plus an epigenetics modifier, maybe we’ll have a real impact on cancers that have been harder to treat and were pretty resistant to traditional chemotherapy drugs alone.
Call Leader: Okay great. Looking a little broader, just with all these new drugs that are probably going to be on the market in the next one two or three years, like when Vyxeos and Venetoclax and Midostaurin and the IDHes are there, my sense is that there’s going to be a lot of mixing and matching kind of like being like a baker with different patients trying to figure out which is the best combo for their case. Is that accurate?
Doctor: Well, I think so, and I think a secondary group that’s going to benefit from all this hot action in AML finally are the people who provide the testing, right? So the molecular-based testing.
It’s going to be really imperative if you have all these things that you get molecular testing, get it quickly, have drugs available, move drugs forward. The cool thing from my perspective as a drug develop person or a clinical trial person is I think we really need to study these pretty carefully and I think we need to develop smart clinical trials that gets us answer quickly, where we utilize 30 or 40 patients to get a real answer. We need to do that better so that we can have access to these drugs and these combinations where we can learn if we get any crazy toxicities, and we can learn what’s expected as far as response rates.
We’re not there yet. We’ve got to study it more, we’ve got to have the resources in place to know what the mutations are in real time. We’ve got to understand whether those mutations are really the ones driving the leukemia or are they just riding along, are they passengers? So there’s a ton, a ton of work for people in my space and ways to think about this so that we can effectively and efficiently move drugs forward and have the best chance of impacting patients with these terrible diseases.
Call Leader: Great. That’s very helpful.
Doctor: That may be pie in the sky, but I think it’s not unrealistic that we’re going to be able to do some of these things for some forms of our leukemia.
Call Leader: Yeah, I know, I think ... Yeah, it might take a few years, but it seems like we’re going in the right direction. So, I was just wondering what do you think of the prospects for CAR-T for AML. I know there’s been difficulty in finding the right target for CAR-T.
Doctor: Yeah, yeah. I think that’s the problem. You said it. There are some markers that seem to be on stem cells and not so many other cells are not ... Sorry, cancer cells are not regular hemopoietic stem cells.
One of the ones that people talk a lot about is CD123. What I envision with CAR-T cells is if there would be a way to deliver the CAR-T cell and then have it die, so not produce the memory of ... You certainly want a memory to prevent people from relapse, but if you can develop a CAR-T cell as a cytotoxic, to hit those targets, you wonder if you could give somebody a therapy and then if they weren’t recovering their counts because it was hitting off target effect causing trouble or if they were getting into side effect trouble, that you could quote-unquote kill the T-cells, that is an interesting concept to me. I’m not sure we know how to do that yet, but it’s just something in the back of my mind, like if you had a maintenance drug and you said every six months I’m going to give this, let it work in the patient’s body for three weeks.
It might cause some cytopenias, because it might ding their regular stem cells, their hemopoietic stem cells, but then I just put in the suicide gene and after three replicates it dies.
You wonder if something like that could be created in a very innovative space. I don’t know, but certainly if you have a target that’s of interest for a leukemia, but could have secondary problems on other tissues, there may be a way to do that that could help patients.
Call Leader: Yeah, the funny thing is even though we’re ... I think we’re relative close to a CAR-T approval. It’s still really early days for the space, so you know, it’ll probably be ... CAR-Ts in ten years will probably be very different than today.
Doctor: And they’re toxic. They’re pretty toxic right now, so some programs are put on hold or slowing down because of the toxicity that people aren’t quite ready to manage, so we need more work in that space for sure.
Call Leader: Just moving onto another, a little more off the beaten path therapy. Did you have any thoughts on Iomab-B? It’s basically a beta-emitter for use as a conditioning agent for HSCT.
Doctor: I do. My stuff’s not so super-duper meaningful, my comments. But efforts to radio-label and deliver hopefully lower-toxic drugs for prep regimens or for anti-tumor part of the prep regimen is certainly something of interest to folks.
The downside is that these are a little bit complicated to give they’re complicated to make, they’re complicated to deliver. There’s a big timing factor, I mean big timing part of this, so an institution has to be pretty aggressively geared up to want to study these types of compounds because there’s a whole process of getting the drug and getting it labeled and having ... it to have effectiveness.
There’s a big timing component to it, so a program really has to be geared up, or it has to have the resources allocated to really take care of the patients, to get these radio-labeled antibody type conjugates so, I think they’re interesting. Maybe they’re not as [inaudible 00:39:29] as may be. I’m not sure I’m as bullish on them as I’ve been on other things in the past, but certainly they may find a role for the patient with active leukemia that has a good donor for a transplant, and you really want get them [inaudible 00:39:46] immunomodulatory type approach. I think that that could happen. I think that that would help a lot of patients who are trying to get to a transplant but can’t get there. Where these drugs sort of step in, is they might be able to allow people like that to get to transplant.
Call Leader: What percentage of the market would you estimate that is?
Doctor: I’ll make this up, but let’s say 30%. What I mean by that is, if you could show that you can cure people with less toxicity and transplant works in that setting, whatever percentage of primary refractory patients, 30% right off the top, you might say, “20 or 30% of people don’t go into remission with induction therapy, I don’t have to worry about these other salvage treatments, I’ll just give them this and transplant them.”
So, that’s not even accounting the relapsed patients, or the ... that’s just counting the refractory patients, so it’s a long way to go ‘til we prove that, but if it really worked and if 50% of those patients did well following the transplant and were cured, you’d be hard-pressed to say, “You’re better off giving some other salvage chemotherapy and then doing a traditional transplant.”
I think that there’s a potential large chunk of the marketplace out there depending on the indication that’s available to them and depending on the ability to deliver the drug in the transplant setting, I think it’s real, but there’s no data to tell me it’s going to work.
Call Leader: Just in terms of the ... some of the practical aspects you mentioned, do you think that this is something that a community hospital would be able to deliver?
Doctor: Community hospitals don’t do a lot of transplants. If you said to me, “Could any place that does a transplant, does allogeneic stem cell transplants, would they have the capability of doing something like this?” I would say probably yes.
There’s going to be bigger centers that do have department of radiation and oncology, and they’re going to have access to probably the right things, isolation, etc, etc. But would community practices use it? I’m not thinking, off the top of my head, they would, but that would be a large resource allocation issue for them.
I may not be thinking about that fully and clearly, but off the top of my head I would say I wouldn’t think so unless I’m missing something.
Call Leader: Okay, great. Just thoughts on one more drug, and that’s the Seattle Genetics has that anti-CD33, recently had a clinical hold related to hepatotoxicity. It’s been lifted, but any thoughts on the drug and is that toxicity a concern for you?
Doctor: Any time there’s a clinical hold for a drug that’s got real activity it makes you a little bit anxious, and we know that there have been other drugs that have had liver toxicity, that have thought to be pretty exciting and then they ... we ended up having them taken off the market like the [inaudible 00:43:38] drug years ago, so I think that it’s certainly a concern.
I think that the stuff that came out of ASH last year suggests that they have some good clinical activity, and again we’re just going to have to figure out which patients benefit from it, which patients get hurt by it, and how we can give it in a safer manner. Maybe it’s a scheduling thing, maybe it’s a ... there may be other issues involved, so I think more sorting out, it seems like there’s some level of clinical activity with this and we know that other drugs in the 33 space have activity, so I’m not surprised or shocked that there’s some activity, but I think that we need to be very careful moving drugs with toxicity signals early. We just have to thoughtful about that.
Call Leader: Great. Just wanted to wrap up with one final question that’s just outside of anything we’ve talked about, what’s really exciting you out there?
Doctor:  I’m excited that we seem to have a good paradigm pathway that’s worked out, meaning targeted therapies in combination with traditional therapies. There seems to be a reasonable strategy to look at these drugs. I’m excited by that.
I’m not saying it’s the best drug of all the world, but I think the Venetoclax stuff is pretty cool. We’ve wanted to figure that out, that BCL2 paradigm, and I think that that lends itself to more investigation of anti-apoptotic signals and how to manage them, so I think that’s pretty exciting from that standpoint.
I like the idea that if we can get molecular testing, we can figure out the mutations quickly that we might be able to build more effective therapies by adding the right inhibitor to the right combination to the right cocktail. I think that feels like it’s pretty exciting. And I think that there’s lots of work for most of us to do to really explore these in a little bit more detail. To optimize and to build on the responses that we see, so all of those things together make me feel like it’s a relatively fun ... For years it’s not been that great to be in the AML drug development space. We haven’t had that much success, but the next couple years, we may have a few drugs that are approved that we can begin to integrate into our standard approaches, and that might really help our patients.
Call Leader: Alright, great. I’ve actually had a couple of questions sent to me from the Slingshot community. What percentage of patients with AML receive 7 plus 3 or another aggressive regimen and how many receive HMA or a low-dose therapy?
Doctor: I don’t know if I know that data. I can sort of extrapolate a little bit from our group. The median age of close to 70 would suggest that half the patients would be given a demethylating drug, but it really doesn’t work that way. I think there’s plenty of early 70-ish patients that we’d want to give. My guess is that if you look at all of AML, ARC-based regimens probably in the U.S. be 60% and demethylating drug approaches maybe 40%.
I’m sort of guessing and hedging that one but I still think ARC probably is used more frequently, and I fail to say that most people don’t even treat, they just sort of say” “We’re not even going to treat you with anything because you’re too sick and too old,” so that certainly happens as well, so maybe it’s 10% don’t get anything, and 40% get a demethylating drug, mostly the older folks that are pretty frail, and 50% get ARC-based something or other.
I’m not sure you should rely too much on what I’m saying, but that’s sort of what I when I think about it, because even some 72 and 73 and 74 year olds do get 7 and 3 at lots of institutions. It’s probably pretty close, but it may be in favor of ARC based regimens.
Call Leader: Okay. Just one final question is, how do you see MRD evolving in AML and what roles do you anticipate it will play in the next three to five years.
Doctor: MRD is interesting because MRD may give you a closer view of the mutations driving the stem cell population, so I think that we want to study MRD at both the phenotypic, cell-surface markers identifying them and the genotypic if you will or molecularly to see whether or not these sub-clones that may give rise to leukemia in the future.
I do think that we are wanting to incorporate MRD and study of MRD into our trials and into our research. It’s hard to do it’s a small population, so it’s easier said than done but I think that that is something that will be important. Help us the biology of the disease, and help us think more aloud about what ... Should we be adding something ... Something [inaudible 00:49:57] MRD. Most MRDs data would show they’re going to relapse, so is there something we can add at that point to improve that, to minimize it, to stop it from progressing. Again, if we understood what those cells were, what mutations they harbored, maybe we would be able to do something low toxicity with high efficacy.
Call Leader: Okay, great. That’s all my questions for today thank you so much. This is extremely helpful.
Doctor: I’m glad it worked. I appreciate your time and let me know if there are other questions that come up you can certainly probably reach me through Joe or any of his team, okay?
Call Leader: Wonderful. Thank you so much.
Doctor: Yeah, be well.
Slingshot Admin: Thank you gentlemen.
Call Leader: Yeah, you too.
Slingshot Admin: Thank you gentlemen, I appreciate the time today. Have a good afternoon everyone.
Call Leader: Thank you Joe.

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