Introduction

DR LOVE: I’m Neil Love from Research To Practice, and welcome to Consensus or Controversy, our outstanding faculty talks about clinical practice patterns and available clinical research in the management of acute myeloid leukemia. We have a fantastic faculty for this program, Drs Mark Levis, Dan Pollyea, Sasha Perl, Eytan Stein, and Andrew Wei. And we have also Dr Courtney DiNardo, Alice Mims, and Eunice Wang, who contributed to a survey that we’re going to show you in terms of practice patterns that these investigators have in AML.

We’re here to talk about AML, and particularly practical clinical management issues, particularly as it relates to community-based oncologists.

Here’s where we’re heading. These are the 5 areas that we’re focused on in the presentations. We’re going to start out with the faculty person who did the presentation but then try to get input from the rest of the faculty.

Optimizing the Management of AML in Older Patients or Those Ineligible for Intensive Chemotherapy

DR LOVE: Andrew, in his talk, discussed the management of AML in older patients and those ineligible for intensive chemotherapy. And I thought I wanted to start out with this first slide in your presentation, Andrew, and let you comment on this thought that you put out there in terms of life expectancy of older people and how it relates to AML.

DR WEI: I thought it’s just a reminder to me and everyone that when we talk about clinical trials and we look at, as you can see in this slide here, with improvement in survival often measured in months, that even for a 75-year-old that their expected survival if they didn’t have leukemia is potentially measured in many years and sometimes more than a decade. And so I just wanted to keep this in mind for all of us, that we are making progress, but we are at the beginning of a long journey in terms of trying to cure people.

DR LOVE: And Mark, this was actually another slide that Andrew had in his deck, a really great overview in terms of what’s been going on in AML. I can remember a few years ago we tried to do a CME program. There wasn’t that much to talk about. Now in an hour and a half we’re going to be racing through things like crazy. We won’t even cover everything. Any comments on what’s been going on these last few years, Mark?

DR LEVIS: Well, I think all the color that you see on this slide is indicative of the color in the field all of a sudden, a bewildering array of choices now, particularly for the older patients, as Andrew was mentioning. What do I do? Wait for mutation or not? Oh, it’d just be easier to do this one. No, no, I’m going to wait for the targeted agent. Which targeted agent would that be? You might have 1 or 2. And the target agent might be selective for 1 mutation or it might be broadly targeted, venetoclax or glasdegib. So color and confusion, and perhaps controversy.

DR LOVE: And so we’ll see if we can shed a little light on what has become a pretty complex set of clinical decisions. And Andrew, of course one of the major advances has not only affected the field, but really affected general medical oncologists in community-based practice because now we’re talking about older patients that they often might manage by themselves. And of course we’ve seen the incredible infusion of the venetoclax combination trials, both with HMA as well as low-dose ara-C, and on this slide you compare some of the outcomes.

Before you kind of get into that maybe just to take a step back, Andrew, in terms of the background in terms of the work that preceded the use of venetoclax in these combinations. What led into these randomized trials?

DR WEI: The journey actually started way back in 1988 when the function of BCL2 was first discovered, so it’s been almost 30 years to go from the discovery of the target, its function, to a drug and a randomized trial, which has demonstrated efficacy, particularly with VIALE-A trial. So you can see here that the response rate’s clearly superior to conventional therapy historically used, and also the true complete remission rate. You can see the duration of CRs. Interestingly similar with these 2 backbones, 17 months.

If you look at the different subgroups you can see there that a majority of the situations with IDH, FLT3, and TP53 in particular an advantage with azacitidine as a backbone. With NPM1 the situation is perhaps a little bit less clear, where low-dose ara-C plus venetoclax has a response rate of 79%.

DR LOVE: So maybe you can comment a little bit about some of the uncertainties involved when you’re targeting BCL2 in AML.

DR WEI: Sure. So one of the questions is what is BCL2 inhibition doing, particularly as a single agent? We had a response rate of 19% in the relapsed/refractory trial. And so this is a trial that we did where we used a 7-day window of venetoclax as a pre-phase prior to chemotherapy. And it was interesting from our point of view. You can see that the patients that had single-agent responses, particularly clustered in the NPM1, IDH2, and SOSF2 mutant subgroups. And interestingly these are the 3 subgroups which actually do really well with combination therapy, so I think that’s telling us something about the contribution of targeting BCL2 in these entities.

And you can see some of the other uncertainties that I’ve listed on the left here. A patient with myelofibrosis. I think I just wanted to highlight some caution because these people perhaps have a lower degree of normal progenitors, and you can get really severe and prolonged hypoplasia if you give ven combinations to people with severe myelofibrosis. Also, we’re still trying to understand what’s the optimal dose of venetoclax in the context of using antifungal agents, particularly strong CYP3A4 inhibitors.

And there’s variations of whether to use 50 of ven, 70 or 100 mg of ven. And also I think the 2 future frontiers are what happens when people fail prior hypomethylating agents because ven/aza wasn’t done in the context of people who had prior aza, although there was a presentation presented last year where there was a response rate of 40% with ven/aza. And also MD Anderson has a publication where people that fail ven/aza, the median survival is only about 2 1/2 months, so really this is a critical future unmet need.

DR LOVE: So Dan, I can vividly remember doing an interview with you, I think it was 2 years ago, maybe 3, but certainly not a long time ago, before I even heard about this, and you presented a patient who’d been on one of the early trials, and my eyes were wide open. One of the things I found so interesting was some of the biology behind this. Can you comment on that, Dan?

DR POLLYEA: Yeah, Andrew did a great job summarizing some of this, and I think the journey from discovery in the 80s of BCL2 to now is just an incredible process. In addition to the canonical function of BCL2 as a protein that is protected from apoptosis and overexpressed in cancer cells and therefore a logical target in cancer, it’s also been a theme for the last 10 years that BCL2 is overexpressed in the leukemia stem cell compartment. And we think that a big part of the activity here is the ability of venetoclax to target that very difficult and otherwise resistant population, and that can lead to deep and durable responses.

DR LOVE: So this is another slide from Andrew’s deck, Sasha, looking at some future directions. I’m curious where you see things heading, Sasha, with this agent. I’m particularly curious about CC-486, so-called oral azacitidine. And whether maybe someday we’ll be moving towards all-oral therapy. Any thoughts, Sasha?

DR PERL: Well I think it’s been really exciting to see more of AML therapy go from inpatient to outpatient therapy, in general, and venetoclax HMA really falls into that area. But the question really is just how often do we need to bring the patient into the office to get infusion versus could we do all of this with pills. I think patients, when possible, prefer oral agents over needing to come into the doctor’s, especially if they’re well tolerated agents.

And thus far we’re still answering a bunch of questions about the oral azacitidine, which is not bioequivalent to IV or subq azacitidine, but the oral decitabine was designed specifically for that purpose, and that seems a logical drop-in replacement for decitabine in this setting. Now we don’t have the safety data or the efficacy data in this particular combination, but one could envision that in the near future. I think that’s potentially a very important development for patients in terms of moving, where they get they’re therapy, from primarily the hospital to primarily the office to primarily at home, which a real good advance for many patients in terms of their quality of life.  

DR LOVE: Andrew, I’m curious what you think the next step might be to improve outcomes, and whether you see a role for venetoclax in younger patients receiving intensive therapy in the future.

DR WEI: Yes, that’s been actively examined. And so at this year’s ASH, in fact, there are some abstracts showing venetoclax in combination with 7 + 3, with cladribine, with CPX-351. We recently published a paper in JCO showing 5 + 2 in combination with venetoclax. I think we can expect very high response rates, particularly in de novo AML. With secondary AML, particularly with prior HMA exposure, I still think this is a problem, and intensification of therapy may not be the answer.

And I think in the future it’ll be a combination of getting patients into remission, reviewing what they’ve got left in terms of targetable mutations, and I think adaptation of therapy in the future is going to be the way to go, rather than just using a one-size-fits-all approach until the patient relapses. So hopefully in the future we can detect disease before patients clinically relapse with rising MRD and change therapy along with the disease changing. So I think those would be the future areas of interest, from my point of view.

DR LOVE: So let’s get some input from the audience now, and Eytan we’re asking the audience here in general how they might manage a patient who’s 80 years old with AML, intermediate-risk cytogenetics. Audience, what’s your usual approach to a patient like this?

And Eytan, while we’re looking at that I’m curious, Eytan, how you would think this one through. And are there situations in younger patients where you think about going to venetoclax, for example, rather than intensive chemotherapy? In terms of the older patient, we can see that — I call this a consensus.

And actually our audience is almost the same, actually 10% low-dose ara-C, interestingly enough, but the vast majority saying aza and venetoclax.

Eytan, what are some of the situations where you might think about this in a younger patient, even now?

DR STEIN: Yeah, so that’s a great question. So we know that some patients who are younger are biologically unfit for chemotherapy. And what I mean by that is that they have a collection of cyto or molecular genetic abnormalities where they’re anticipated response to induction-type chemotherapy with 7 + 3 or FLAG or something like that would be in the 20% to 30% range. And that might be a group of patients who we may be able to get into a complete remission at a higher rate with azacitidine and venetoclax.

I also think that you’re going to be seeing, over the next 2, 3, 4 years on clinical trials, trying to push that aza/venetoclax age down from the 75 and older, or patients younger than 75 with comorbid conditions, really pushing it down to younger and younger ages, even if they have intermediate-risk disease.

DR LOVE: So Mark, in terms of subsets, here’s another question we asked the faculty, again an older patient, but now with poor-risk cytogenetics. And again we still see aza/venetoclax. Mark, can you comment on some of the subsets in AML and where you think more about this combination? And what about in situations where you have a potential target such as IDH or FLT3, Mark?

DR LEVIS: The problem with aza/ven and the good thing about aza/ven is in fact you can give it to everybody without having to think very hard about what target they have. And I find myself lecturing to my fellows. Well no, we’re going to wait until we find out whether there’s an IDH mutation or whether there’s a FLT3 mutation. Nah, let’s just give aza/ven because in fact the initial response rate is so good kind of across the board, and so to be honest, I tend to reach for this combination initially in just about everybody who fits the category of I’m not going to give you intensive therapy, and then tailor it down the line as I find out what mutations they have.

The 1 subset where I am actually keen to identify early on are these complex karyotype TP53-mutated cases. They’re not going to do well with intensive therapy. So even in a younger patient who frankly might be more fit, I will tend to look for an excuse to hold off until I’ve ruled out that subset. But for the most part, this is kind of an easy regimen to start with.

DR LOVE: So Sasha, on that list that we showed earlier that Andrew put together in his slide of new agents was also glasdegib, and I’m curious what we know about that in AML and whether there are any situations where you use it.

DR PERL: It’s a hedgehog inhibitor. It’s been looked at as a single agent and in combinations. It’s approved in combination with low-dose cytarabine. And right as that came out, almost exactly at the same time, was when the aza/venetoclax approval happened, or the venetoclax/HMA approval happened.

And so the question in the US, where we’re more keen on using HMAs than low-dose cytarabine, and the efficacy data seen on those studies was would people vote with their feet as for one regimen being better than the other. It’s effectively the same population. The response rate looks higher with ven/HMA or ven/LoDAC. So very few people have actually used glasdegib. Now that’s not to say that it’s not an active agent, doesn’t have benefits, it’s just we’re hard put to say a regimen with this high a response rate, and actually with a Phase III study showing a survival advantage over HMA, should be substituted with a novel combination regimen that’s low-dose cytarabine based.

I have not personally used it really in my practice, the glasdegib/low-dose cytarabine combination. The times I think about using it, however, in people, as Andrew said, who’ve had prior HMA, where we don’t have as much confidence that the HMA/ven combo is going to work as well as it would in somebody who’s naïve to HMAs. In that setting, I think it might be reasonable to try it out. Again, Mark mentioned p53-mutated patients, where we really don’t know what the right answer is, we’re largely steering these people to trials.

And to echo off of something that Dan said, this may be a drug that targets leukemic stem cells. So whether it’s ideal combination is low-dose cytarabine or with other combinations I think is anybody’s guess. It’s an interesting drug, it’s an active drug, but I don’t think it’s currently getting a lot of use.

DR LOVE: So I want to finish out this section by hearing about one of the cases you discussed in your presentation, Andrew, this 78-year-old lady. What happened there?

DR WEI: Yeah, this lady was interesting and also illustrative for several points. So first of all, the patient had an obviously very good remission with venetoclax and low-dose ara-C. But the interesting thing is that after about 15 cycles, she said look Andrew, what about ceasing treatment? Do you think that’s possible? And I examined her bone marrow. I couldn’t find any evidence of disease, yet she still had this IDH2 mutation. We know that IDH2 mutations don’t always represent leukemic clones. So we decided to stop therapy. And lo and behold she maintained a remission, treatment free, for almost 4 years.

She eventually did progress, and in addition to the IDH2 she developed an SOSF2 mutation. We gave her an IDH2 inhibitor, she achieved a response, and then she progressed afterwards. And then she had a new FLT3 mutation, which we had not detected at any point in the many years of her disease history. And so this illustrates the plasticity of leukemia and the importance of looking for new targetable mutations at each disease progression point.

So my learning points here were yes, in some people we can cease therapy. We need studies to see whether a treatment-free interval is something we should or should not do, and after how many cycles, furthermore looking for clonal evolution. And in these older people the illustration that we can treat relapse without chemotherapy with these new targeted agents, keeping patients out of hospital, whilst maintaining some degree of quality of life.

DR LOVE: And of course a couple hours ago when we were talking about venetoclax, usually with obinutuzumab in CLL, there they stop therapy after a year or 2 depending upon the situation.

I’m curious, Mark, what your thoughts are about this case. Really fascinating in terms of how targeted therapy ended up being part of the picture here, and also how you get IDH without it being a nonmalignant clone, incidentally, Mark.

DR LEVIS: So I don’t know that I agree with the phrase it’s nonmalignant because it sat there for 3 years, but I have to confess when I see the IDH2 mutation sitting there, here in the US I will tend to put on enasidenib and let the patient stay on that as a maintenance drug. Do I have any evidence for that? Not really, but in fact we have looked at this, at least at our center, with these IDH2- and IDH1-mutant patients. We will tend to find that patients who get this drug stay in remission longer if they have the mutation. In other words, just correlating the drug seems to have efficacy in the remission state. So we are tending to use it in a maintenance setting. Now we’re studying that in trial form as well.

Treatment Options for Patients with AML Harboring FLT3 Mutations

DR LOVE: So we’re going to move on now and talk about our second module. We won’t be able to go through every point that Sasha made, but I want to kind of get into a few. And maybe we can just kind of start with a quick overview of the biology of FLT3 mutations, Sasha.

DR PERL: Sure. It’s a receptor to tyrosine kinase. It’s mutated in about a third of patients with AML. These mutations clinically associate with a high white count, a high blast percent, and proliferative disease, the white count rises quickly. Genetically we often see this in intermediate-risk patients, often with NPM1 mutation and a normal karyotype. You can see the same mutation in APL. It’s not prognostic there, although it associates with high white count.

And it’s often subclonal. It’s a late hit in oncogenesis, and so that led to many people thinking it wasn’t a very good target. But actually if we look at some of the most successful targeted agents in AML they are drugs targeting FLT3. And in particular in relapse, the relapses can be very driven by FLT3, and drugs that potently inhibit FLT3 function and inhibit the tyrosine kinase can be quite active and have shown to be superior to alternatives.

DR LOVE: So I’m kind of curious about this. This is a really interesting slide you also discussed. Can you comment on that?

DR PERL: Yup. So basically we know a handful of ways to improve the survival of patients with a FLT3-ITD, which is the most common of the types of FLT3 mutations, and also the most sinister, the one that’s associated with a higher rate of relapse and worse survival traditionally. But traditionally that was with chemotherapy-only approaches that used relatively low doses of daunorubicin. And when we’ve increased the amount of anthracycline into front-line induction, whether that’s with 2 induction cycles to all patients or using a higher dose of daunorubicin on the first cycle, we see better outcomes in the FLT3-ITD-positive patients, and better survival.

So on the left, the high-dose daunorubicin improved survival on the ECOG 1900 study, and there’s a similar result from the UK AML17 study. Around this time incorporation of allotransplant for these patients was initiated, and on a donor versus no-donor study where there was about 80% adherence to that genetic assignment, there’s better survival in the patients who had a donor, suggesting that allo improves survival.

And then most recently the addition of a FLT3 inhibitor, midostaurin, improves survival compared to placebo on a study where patients were given 7 + 3 plus a third drug. And so the addition of midostaurin importantly improves survival not just in FLT3-ITD, but FLT3 tyrosine kinase domain mutations, as well. And really anybody who is fit for induction chemotherapy should be receiving intensive induction chemotherapy plus a FLT3 inhibitor as standard of care. The question now is what’s the best front-line FLT3 inhibitor, and that’s being addressed by randomized studies.

DR LOVE: And Eytan, maybe you can comment a little bit about what we know about the available and being studies FLT3 inhibitors.

DR STEIN: Yeah, absolutely. So gilteritinib, as Sasha’s going to point out, has been approved for the patients with relapsed and refractory FLT3-positive acute myeloid leukemia. Midostaurin is approved, but only in combination with induction and consolidation chemotherapy for newly diagnosed FLT3-positive acute myeloid leukemia. Quizartinib is a very interesting story, which is too long to get into now, but it was studied in a randomized Phase III study which actually showed a small survival benefit but then went to the FDA and was rejected by an ODAC committee. And crenolanib is a Type 1 inhibitor that is also being studied in ongoing clinical trials in a variety of settings.

DR LOVE: So Andrew, Eytan referred to gilteritinib, and of course the ADMIRAL trial is really what got it approved. Can you comment a little bit on what was seen there and what you’ve seen clinically with this agent?

DR STEIN: So I think this was a really important trial, which Sasha published in New England, and they looked at patients with first relapse with respect to FLT3-mutant AML and basically put a tablet, gilteritinib, against whatever the physician wanted to give, be it low-dose therapy or even intensive chemotherapy. And I think one of the most interesting aspects of this study, where the gilteritinib looked better than giving intensive chemotherapy in patients with relapsed FLT3-mutant AML.

The other major aspect of this trial were the patients were taken to transplant. And patients did quite well after transplant, including those that received gilteritinib post-transplant. And the other interesting feature of this trial, I thought, was that patients with a triple-mutant, which I call the triple mutation of death, DNMT3A, NPM1, and FLT3, who normally do catastrophically poorly with any treatment, this agent actually did the best in that subgroup. So I thought those were the really fascinating aspects of this trial.

DR LOVE: So coming back to you, Sasha, in your talk you go through a bunch of the key clinical and really research issues that are being discussed right now, in which you call the FLT3 world. Can you talk about that?

DR PERL: Yeah, I think, as has been mentioned before, we know a lot more about how to improve outcomes for patients with FLT3 inhibitors and other therapies now than we did years ago, but that doesn’t mean that this is a solved issue. We still would not say that outcomes in these patients are ideal. And we still see a lot of relapses despite all of these advances.

So how best to improve outcomes for these patients? Some of the questions that I think we’re still trying to answer right now are listed here, and questions that I deal with daily in terms of managing these patients, including is this really the best therapy for patients other than the vast majority that we see, ie those with intermediate-risk karyotype? What should we be doing for patients who have favorable-risk karyotype from core binding factor rearrangements but have a FLT3 mutation? What would be the best drug to add to 7 + 3 there?

In our institution, we are often looking to give gemtuzumab. Should we be giving a FLT3 inhibitor to those patients? What about FLT3-TKD patients? How much benefit do they see from midostaurin? There was a recent publication that looked at this in various different subgroups of the ELN classification. And it turns out it’s different depending on the ELN classification. Those patients are very much enriched in the core binding factor and otherwise ELN favorable group, and they seem to see quite a bit of benefit there, but maybe not as much as GO. And those in the ELN intermediate- to adverse-risk group may see a little bit more benefit there and really should get the drug.

Who needs transplant is a big question now because the ELN has classified patients with FLT3-ITD at a low allele burden and an NPM1 mutation as having a relatively favorable outcome? But on the RATIFY study that showed the benefit, a lot of patients went to transplant, more than 50% of patients on that study were transplanted.

And now we’re looking at the question of is it enough to give a FLT3 inhibitor prior to transplant. What about giving it after transplant? There’s 2 randomized studies showing a survival benefit, either in disease-free survival or overall survival, giving sorafenib post-transplant to patients who had an allotransplant. And that’s been addressed in a Phase III study of gilteritinib versus placebo that just completed enrollment in the last year. So we hope to have a little more statistically robust data on this.

Just to finish up odds and ends, what about older patients who have FLT3 mutations, but as Mark mentioned, could be candidates for venetoclax/azacitidine? Should they be getting a FLT3-TKI-based regimen or a ven/HMA regimen? I don’t think we know the answer to these things yet. And I think these are important questions still to be answered in trials going forward. We don’t know everything about the best way to treat this group. It’s still a lot of unanswered questions.

DR LOVE: So Mark, we could spend a long time talking about this slide, but I’d just like to get your thoughts, Mark, on some of these questions, particularly the issue of maintenance therapy, also the important issue of using newer, maybe more specific FLT3 inhibitors. We know there’s a big trial certainly looking at gilteritinib that we’re looking forward to see. And this third question about the unfit patient with FLT3. Mark, any comments?

DR LEVIS: So the maintenance issue is a big one because our current data on maintenance after transplant took patients that went to transplant usually without a FLT3 inhibitor. If you had a FLT3 inhibitor-induction chemotherapy you get a deeper remission. I think that data is becoming clear.

If you have a deeper remission when you go to transplant, you’re more likely to be cured. Do you really need maintenance afterwards? Why not? Maintenance is perfectly safe? No, it’s not perfectly safe. Actually, I just had a patient call me getting another big, whomping skin cancer on gilteritinib. And I’m definitely seeing those pop up.

But TKIs are not safe to be on for decades. When do you stop them? And so actually I think one of the interesting things about the post-transplant maintenance trial is, at least in the US patients, most of the patients are going into that transplant having received 7 + 3 plus midostaurin, vast majority. We’re actually going to get an idea of whether or not maintenance really works or is of any use in those patients. They may be cured, or a large fraction of them may be cured.

The older patient population is what really vexes me. What do you do with these 80-year-olds coming in with classic DNMT3, NPM1, FLT3? Okay, yeah, they go into remission with aza/ven, and then I’m trying to sort out how I deal with FLT3. We know that they’re going to relapse more rapidly with aza/ven maintenance. So we’re kind of all making up stuff. I’m switching them over to aza/gilt after I get them in a remission with aza/ven, and everybody else is doing something completely different. So what we really need is clinical trial data to find a cohesive approach.

DR LOVE: I call making up stuff the art of oncology.

DR LEVIS: Oh, I love it. I make up stuff all the time.

DR LOVE: Anyhow, Dan, this is an interesting slide looking at the effect of azacitidine and HMA based on subset, and you see the arrow going to FLT3. Any comment on the approach to the older patient, Dan, with FLT3 mutations?

DR POLLYEA: Yeah, we were just having a nice sidebar chat about this, and I think it’s a really good topic for discussion. I mean as you can see, the patients that have FLT3 mutations, they don’t really have a problem getting into a remission venetoclax plus azacitidine. And there’s clearly, as you can see, a benefit of that regimen over azacitidine alone. But it really does call into question what is the motive, or what would be the strategy for a FLT3-positive patient up front?

Would we think that the addition of a FLT3 inhibitor could allow for a better response rate? I think in that case even adding a FLT3 inhibitor in the up-front setting to chemotherapy, that’s not really the readout you see. You don’t really see a better response. As we know, FLT3 is important in terms of causing relapse, so perhaps that’s where we just heard Mark’s approach of switching out the venetoclax and doing maintenance FLT3 inhibitor.

I think it’s a really open question, but I also just want to emphasize this slide, that the usual suspects with respect to bad prognostic outcomes that we’ve all come to know are mostly defined in the context of intensive chemotherapy or other conventional treatments. And so things like FLT3, and other issues like secondary AML or bad cytogenetics, may not be as relevant with respect to response or other endpoints with venetoclax-based regimens. It’s just important to keep that in mind.

DR LEVIS: So I might pipe in here with just 1 extra comment on that. I think you can look at the issue in 2 ways. 1) Practically when you add a FLT3 inhibitor to venetoclax hypomethylating agent, I think you’re asking for a deep aplasia. And it’s already an older patient who’s not going to like that. 2) The biology says when a patient presents with leukemia, it’s often the FLT3 part of it is not the dominant component, or it isn’t necessarily driven all by FLT3. You’ve got to address the non-FLT3-addicted clones. Aza/ven works to clear that out, and then you can focus on FLT3, which is why I kind of like the idea of clearing things out with aza/ven first, and then coming in with aza/gilt.

DR LOVE: So Sasha, I want you to take a look at how our faculty responded to a young patient with intermediate-risk AML and a FLT3-TKD mutation. And again, I call this consensus. But I was curious about this one, FLT3-ITD mutation. Almost everybody, but Courtney DiNardo says she thinks about 7 + 3 plus gilteritinib. Any thoughts, Sasha?

DR PERL: Well, we have a randomized trial we’re trying to compare these 2. I think that’s the best way to answer it. We will be presenting final results from a clinical trial, a Phase I/II study combining 7 + 3 plus gilteritinib. Keith Pratz is giving that talk this ASH, so look for that.

But it’s an incremental advance upon what we’ve presented from that trial previously that shows it’s feasible, and that’s why we’re able to compare it in a head-to-head trial against midostaurin and see what the right answer it. And I think that trial, as well as a larger study that’s a Phase III that’s ongoing in Europe, will really answer the question of what’s the best FLT3 inhibitor you can give front line. Which, as I mentioned before, is a really important question to answer.

We just don’t know. It is possible that the selectivity of gilteritinib missed the point that Mark mentioned before, which is there’s other stuff that you have to hit with broader kinase inhibition that contributes to the mechanism of action of midostaurin, which is, as far as I can tell, unspecified in front-line leukemia. It’s not a drug with single-agent antileukemic activity in relapsed/refractory patients. And we don’t know that it’s just working as a FLT3 inhibitor front line. So that study will be helpful.

DR LOVE: So Andrew, I’m going to ask the audience a question relevant to what we’ve just been talking about. Audience, if you have a 78-year-old patient in good condition, intermediate-risk AML with a FLT3-ITD mutation, what would be your usual approach to treating a patient like this?

And see what the audience would do, we’ll take a look at kind of what everybody else is doing. Andrew, I was interested by your answer, aza/ven and gilteritinib. Can you comment?

DR WEI: I think as Mark has alluded to, it highlights our anxiety about FLT3-mutant AML, particularly with azacitidine and venetoclax because FLT3 mutations can drive other prosurvival proteins, like NCL1 and BCL-X, and that could be one of the reasons why we sometimes see FLT3 mutations emerge off the back of venetoclax-based therapy as a mechanism of resistance.

And so as Mark alluded to, trying to prevent that FLT3 clone from coming back and causing relapse is the key question at the moment. And there are several ways of doing it. Either you can add a FLT3 inhibitor up front, but then you risk the possibility of cytopenias. You could give it sequentially, as Mark has suggested, either alone, potentially in combination with venetoclax or in combination with azacitidine. I think those 3 options are certainly ripe for clinical trial investigation. Alternatively, you could give the ven/aza, wait for the FLT3 mutation to emerge, and then switch therapy to either gilteritinib or a gilteritinib-based combination.

At the moment, we don’t know which is the correct way of doing it because different selected pressures could induce different resistance mechanisms. And whether that is a good or a bad or a treatable or untreatable resistance, that’s what we really need to find out. So the sequence of what we do is going to be really important to understand in the future.

DR LOVE: And for that poll question two thirds of the audience just said aza/ven, but about a third said aza/ven and FLT3.

Let’s finish out this discussion, Sasha, with a brief review of your 53-year-old lady. What happened with her?

DR PERL: So this is an interesting case. 53-year-old lady who presented in 2017 with typical presentation of FLT3-ITD-mutant AML, presented in leukostasis with a white count of 300,000, was actually a little bit unusual in that she had an isochromosome 17q, which actually leads to a loss of p53. So that’s unusual. So she has high-risk karyotype, as well as FLT3-ITD. And she was induced with 7 + 3, and kind of typical for p53 was refractory.

We gave her 2 induction cycles, and she was totally beaten up after that. She enrolled to a clinical trial of one of the Phase III studies mentioned previously, either a FLT3 inhibitor or standard chemotherapy, randomized to the control arm. She didn’t respond to what we gave her. I gave her sorafenib and azacitidine, which worked quite well for her, and actually she thrived on that. She was able to clear her peripheral blasts, and her marrow blasts reduced enough so that she was stable for transplant, albeit with persistent disease, both in terms of a few marrow blasts and a FLT3-ITD mutation. So really high risk for relapse post-transplant.

Got a myeloablative transplant for an HLA-identical sibling, put her back on sorafenib post-transplant maintenance, and she remained in remission thereafter for years. Full donor chimerism. And then, I assume you’re going to get into the next slide here, what happens after that. So just to say that this patient’s at very high risk for relapse in general because going into transplant with detectable disease is an almost guarantee that your disease will come back after transplant.

Chris Hourigan has a figure in his MRD study, prior to transplant, that showed I think it was 10 out of 10 patients relapsed and died after transplant who had detectable FLT3-ITD going into transplant. And that’s what we figured would likely happen.

That’s why she got maintenance. And she went 2 years before her disease came back after transplant. And the reason for that happening is not just persistence of disease. This woman wound up having chronic graft versus host disease. I treated her chronic graft versus host disease, and it may have been that just turning off her immune system got rid of her GVL. We looked for new mutations there. She was on sorafenib. We often see a FLT3 D835 mutation. She has no new mutations on sorafenib, so we wondered whether she would be sensitive to the TKI is we were able to get her of immunosuppressants.

We did not see clonal evolution in her case. And the optimal therapy in this setting for somebody who’s relapsing on a TKI is unclear. If we look at the data from ADMIRAL we could easily see that gilteritinib outperforms salvage chemotherapy, but very few of those patients actually had a prior TKI. So we don’t have a lot of data to say what should be the right therapy here.

So we put her on a clinical trial of venetoclax and gilteritinib, and she’s done beautifully on that in terms of antileukemic activity. She went into a full CR. She had full count recovery. She re-established full donor chimerism. I’ve been playing around with what to do with her chronic graft versus host disease. She’s had a bunch of infections related to that. But literally she is still in an ongoing remission more than a year out on this regimen, and I think from the antileukemic standpoint I couldn’t have done better with this in terms of how she’s done. Very happy with how that’s gone. I wish we had perhaps fewer infections along the way, but given all the things that could have happened in the past year we’re pretty happy with how she’s doing.

DR LOVE: I’ve certainly seen those relapses like that, Sasha, where you treat the GVHD and boom, after a year they relapse.

DR PERL: Yeah.

DR LEVIS: And you killed off their T cells.

DR LEVIS: Yup.

DR LEVIS: Illustrating A) don’t give steroids unless somebody’s got a gun to your head, and B) you don’t really cure this disease. There were no eyewitnesses. The T cells didn’t do it. The clone is still there.

DR PERL: Well there’s some interesting modulatory data for venetoclax also, so I have no idea if that’s playing into this somehow, but for whatever reason, she’s back in a good remission, and I’m happy to have it. But yeah, you’re right. I think these people probably aren’t cured, and long-term maintenance is the right answer.

Management of Newly Diagnosed and Previously Treated AML with IDH Mutations

DR LOVE: So we’re going to move on now and talk about our next topic, what Eytan describes, I had not heard this term before, as differentiation therapy, I thought was very interesting Eytan. And maybe we can start out with this graphic, Eytan, but can you explain what it shows and what it means? I love the way it presents itself.

DR STEIN: Yeah, so this is what’s known as a circos plot.

DR LOVE: Right.

DR STEIN: And this particularly, this is from a large clinical trial of a large group of AML patients. And if you look at the circumference it gives the relative frequency of each mutation in the whole clinical trial cohort, so you see a lot of patients have DNMT3A mutations. And the ribbons that connect the different mutations show the relative frequency of co-occurring mutations. So as we know, DNMT3A co-occurs a lot with NPM1, and then there are some mutations that really done co-occur much at all.

DR LOVE: Can you talk about why you consider these therapies differentiation treatments?

DR STEIN: Yeah, so IDH inhibitors, and to some extent FLT3 inhibitors also, they work, instead of killing leukemic blasts, they cause leukemic blasts to differentiate to mature neutrophils. It’s exactly what we see when we give ATRA and arsenic trioxide to patients with acute promyelocytic leukemia. And the benefit of differentiation therapy, when it works, is potentially that you’re avoiding that period of cytopenias where some of our patients might succumb to significant infections and bleeding.

DR LOVE: So Mark, this is another slide from Eytan’s deck talking about the various cancer types where IDH mutations are seen. Any comments, and where are we seeing benefit outside of AML, and do you think this is a strategy that’s going to go beyond AML, Mark?

DR LEVIS: Well again, once you leave the happy area of hematologic malignancies you get into these tumors that are derived from epithelial tissue, and those have so many more mutations, they’re so much more genetically complex, I fear that I have somewhat of a despairing attitude towards whether or not a single inhibitor is going to have much of an effect.

In fact, the IDH mutations were first found just about 4 floors above me in this building in 2008 in glioblastoma. We still don’t have an effective glioblastoma treatment, now do we, with an IDH inhibitor. So it comes down to the fact that hematologic malignancies are derived from, I think, mesodermal tissue. They’re like a childhood sarcoma, relatively few mutations, hit 1 or 2 of them you’re going to get an effect. The endothelial-derived tumors are just nasty, multiple mutations.

DR LOVE: So Eytan, maybe you can comment a little bit on some of the clinical data we have for the available agents beginning with enasidenib.

DR STEIN: Yeah, sure. So enasidenib is the IDH2 inhibitor that’s been approved in relapsed and refractory AML, and was approved really based on this data showing an overall response rate of about 40% and a rate of CR plus CRh or CRi of about 30%. When you look at the single-arm trials in relapsed and refractory AML, the medial overall survival with enasidenib is about 9.3 months in the entire population, but if you look at those patients who achieve a complete remission, the median overall survival is on the order of 2 years.

I think what’s interesting about this is that there’s a randomized Phase III trial — I think we’re all used to now, of the reporting of clinical trial data by press release, and that’s common in the COVID-19 era. So this is also reporting of clinical trial data by press release. This is a randomized Phase III trial that randomized patients with relapsed and refractory acute myeloid leukemia with an IDH2 mutation either to enasidenib monotherapy or to investigator’s choice of best supportive care or chemotherapy. And this press release, which is really the only thing we know about this trial, is that it didn’t meet its survival endpoint. The median overall survival was the same in both groups.

Now I think it’s important to note that we’ve all taken care of patients who’ve clearly benefitted from enasidenib. And the question’s going to be when we full trial data who’s benefitting, who’s not benefitting, how do we understand those subsets.

DR LOVE: And also, we have ivosidenib. Can you comment on the data there?

DR STEIN: Yes. So ivosidenib is the IDH1 inhibitor, similar data to what we saw with the IDH2 inhibitor in relapsed and refractory AML, similar rates of CR and CRh together of about 30%. We know that both of these drugs can cause differentiation syndrome, and that’s very important to note. Although there doesn’t seem to be a difference in the response rate in patients who have differentiation syndrome or don’t have differentiation syndrome. So differentiation syndrome is not a clinical marker of response or nonresponse.

And ivosidenib has also been approved really based on a very, very small clinical experience in newly diagnosed patients with acute myeloid leukemia with an IDH1 mutation. And that data showed a remission rate of about 50%.

DR LOVE: What about the idea of, Eytan, of combining these agents with induction chemotherapy?

DR STEIN: Yeah. So it’s very promising. So we presented this data, actually it was just published in Blood, showing that you can safely combine IDH inhibitors, whether IDH1 or IDH2, with induction and consolidation chemotherapy. You get relatively high response rates, whether they’re higher than giving chemotherapy alone is currently unknown. The survival curves, which are not in this deck, but are in the paper that’s published, are actually quite good, showing an overall survival greater than 70% at 2 years out.

This is now the subject of a randomized Phase III trial being conducted in Europe, very similar to what the RATIFY trial was like. And this one is combining IDH inhibitors with induction chemotherapy versus induction chemotherapy and placebo with the primary outcome actually being event-free survival and secondary outcome of overall survival.

DR LOVE: So I want to pose another question to the audience here. Audience, you have a 78-year-old patient in good condition, intermediate-risk AML with an IDH1 mutation. In a second I’m going to ask Mark to comment on how he would think through this situation. Let’s see what the audience is thinking about in this older patient. It looks like the most common answer’s going to be HMA/venetoclax, but there’s a substantial minority who also says HMA/venetoclax and ivosidenib.

Mark, any thoughts? You say iza/ivo.

DR LEVIS: Yeah. Me and Courtney did just because, and no question you could get the same response, if I was lazy and didn’t wait for the IDH result, you’d get a great response with aza/ven, and then I’d probably leave the patient on aza/ven. But if the patient’s got that IDH mutation, and you can get ivosidenib and combine it with azacitidine it is the gentlest induction you can give. The patient doesn’t drop any counts.

Now this is a patient with a performance status of 0, and they probably would do great with aza/ven, so there’s nothing wrong with that. But I really kind of like the idea of targeting the driver mutation very specifically. And I think the IDH1, to me, is different than IDH2, and I don’t think we fully understand why the responses are different.

Now in IDH1, when you inhibit that sucker with ivosidenib you get a seemingly single agent, very durable responses. We’ve got patients on those drugs for years, quite literally. We’ve still got people on the Phase I from 2015 that are still in remission on single agent.

DR WEI: Mark, what do you think about the front-line data with enasidenib where the addition aza didn’t improve the overall survival, whereas with the addition of venetoclax to aza there seems to be quite a bit survival difference? Does that influence you decision at all?

DR LEVIS: No because I have not found enasidenib to be as effective or dramatic. And remember, IDH2 is found in the mitochondria. One question is how effectively do you turn off the enzyme, and does a little bit of 2HG produced locally have its effect. Maybe you need a more potent inhibitor for that. And Eytan can comment on this, I just haven’t seen enasidenib be as effective as I’ve sometimes seen ivosidenib. Ivosidenib I’ve just seen more dramatic responses. They are different enzymes. They’re in different parts of the cell. And we don’t have the Phase III, I think it’s called the AGILE trial.

DR STEIN: AGILE. The AGILE study.

DR LEVIS: We don’t have that result yet. It’ll be fascinating. But I might predict that that will be positive. So Eytan, what do you think? What do you think?

DR STEIN: No. I agree. I’m not going to predict what’s going to happen, but I do think that the AGILE study, which is a randomized Phase III study of aza/ivosidenib versus azacitidine, placebo controlled, will give us that answer.

DR LOVE: So Dan, I’d like to chat just a little bit about the issue of differentiation syndrome, recognition, management. We presented this scenario to our faculty of a patient who has new onset shortness of breath, hypoxemia after receiving ivosidenib for relapsed disease. Three weeks after starting therapy, ground glass infiltrates on the chest CT, ANC of 600, 27% blasts in the blood, and getting prophylaxis with levofloxacin and acyclovir.

Here’s what the faculty recommended, and can you comment a little bit about what typically occurs with differentiation syndrome and how it’s managed? I think it’s interesting too that Sasha brings up the question of testing for COVID-19.

DR PERL: I had a patient test positive. She’s getting it.

DR POLLYEA: Everyone gets a COVID test. It’s always the right answer. But yeah, like Eytan was saying, these differentiation therapies are really interesting. I mean there’s definitely precedence for differentiation therapies and differentiation syndrome, as he discussed, with respect to APL. And it’s funny, when I was training, we used to call it sometimes ATRA syndrome, and then we were scolded that that’s totally inaccurate because now there’s arsenic that can cause differentiation, and now we know there are so many other therapies, as well.

I think the challenge here is one in recognition. Differentiation syndrome is so diffuse. There are so many different associated symptoms, it can be really challenging to recognize. But that’s the key with respect to having a good outcome, is early recognition of it and instituting aggressive treatment, which is bringing down the white blood cell count, if necessary, if that’s a manifestation of differentiation syndrome, with hydroxyurea; most importantly initiating steroids.

And we think with at least the IDH inhibitors, given the relatively long half-life of the drug, it probably doesn’t help too much to stop the therapy. And there are some cases in which it’s a benefit. You want the differentiation to occur because it’s terminal differentiation. The cells will grow, mature, and die. And so early recognition is really the key, but knowing also that like COVID anything can be differentiation syndrome, so you have to really have your antenna up for it.

DR LOVE: So let’s finish out, Eytan, focusing on one of the cases you presented in your presentation. 86-year-old woman with an IDH2 mutation. Pretty interesting history that includes COVID and differentiation syndrome. What happened with this patient?

DR STEIN: Yeah, so I think the point of this slide is that this is an 86-year-old woman, newly diagnosed AML. She had an IDH2 mutation. And the question was should I give aza/ven to someone who’s 86 years old. Is she going to tolerate the cytopenias associated with azacitidine and venetoclax? And because she had an IDH2 mutation, and the responses are very good in that subgroup of patients, I did opt to give azacitidine and venetoclax.

And she did quite well, but then she got COVID pneumonia. She actually, this was in March or April when things were really bad in New York City, she actually survived. But she was really quite ill afterwards, having like a post-COVID syndrome, and I didn’t think she could tolerate aza/ven at that point. I put her on enasidenib, and she had relapsed, obviously, and when I put her on enasidenib it took her about 4 months, but now she’s actually back in a complete remission, an MRD-negative complete remission.

So it shows that you can actually give these therapies sequentially. We’ve talked a lot about — in the chat box there’s been a lot of questions about triplets, should we be giving triplets. Maybe it’s better not to give triplets. Maybe it’s better to give these drugs in sequence rather than all at once.

DR LOVE: So interesting. Any considerations in terms of therapy as it relates to COVID, Eytan? We were talking in our CLL section about whether or not anti-CD20 antibodies affect the course with COVID, whether it affects vaccination response. Any thoughts about that, Eytan?

DR STEIN: I don’t think, I mean I don’t know, obviously, but I don’t think that any of these things like IDH inhibitors should affect vaccination response. There’s all sorts of interesting data that a lot of anticancer therapies, or small molecule inhibitors, might treat COVID. I mean there’s data with BTK inhibitors. There’s actually data with dihydroorotate dehydrogenase inhibitors. So any drug you can think of that works for something else seems to work, at least in the laboratory in a dish, for COVID-19 pneumonia.

DR POLLYEA: But Neil, just real quick, you know what does decrease the immunogenic responses is chemotherapy.

DR STEIN: Right.

DR POLLYEA: We’re so focused on these great nonchemotherapy treatments, and I think ultimately that’s a good thing for the COVID world too.

DR LOVE: What about neutropenia, Dan? Any thoughts about that? A lot of docs are generally trying to avoid inducing that with chemo. Any evidence specifically that it increases the risk for COVID or COVID complications?

DR POLLYEA: Yeah, I don’t know about that, but it was definitely interesting. From across the pond in the spring our colleagues in the UK put out some really nice guidelines about treating AML in the COVID era. They made some pretty bold recommendations regarding use of less intensive therapies, even in patients who in another world were good candidates for intensive regimens, out of consideration for the uncertainties around COVID.

And what I take from that is really if we’re going to consider sparing our patients the toxicity of chemotherapy in the worst of times, maybe it’s something we should also continue to be considering in a post-COVID world in the best of times. So I think that is going to have an impact on the way we treat people going forward.

Tailoring Induction and Maintenance Therapy for Younger Patients with AML without Targetable Tumor Mutations

DR LOVE: So Mark in his talk reviewed a number of issues, but one, Mark, that we haven’t specifically gotten into yet is the Phase III VIALE-A trial. Can you comment on that?

DR LEVIS: Well, that was the one where everybody breathed a big sigh of relief because we’d been doling out aza/ven or decitabine/ven or something confidently announcing that this was going to yield us a positive result. Oh my goodness, it actually did, announced first with a press release of course.

So here was patients aged 75 or older or what we called unfit. The patients I put on it, I have to say, were pretty darn unfit. I’ve got an 84-year-old guy who’s still on it, walker and all that. And they were randomized 2:1 aza/ven versus aza/placebo. The nice thing about it you really couldn’t tell this drug from placebo. I mean the way you knew they were on the venetoclax is when they flew into remission in 4 weeks, which they don’t do on azacitidine.

So 2:1. It enrolled very quickly, and we see this very nice — the median overall survival for the aza/ven arm was a little shorter than what we had seen in the Phase II, but nonetheless it was a nice improvement over placebo. And in fact, my 84-year-old guy is one of those little ticks out there just beginning to plateau. So anyway, this was a big relief, and I think it also solidified this big sea change in the field.

DR LOVE: Andrew, any comments on this? And also your VIALE-C trial with low-dose ara-C.

DR WEI: Yes. I agree with Mark that this was pivotal. If this trial was negative, then I think we’d be back in the prehistoric ages. But with this trial being positive it just opens up so many doors because venetoclax can combine synergistically with so many different drugs. We’ve already heard about FLT3 inhibitor combinations. Courtney DiNardo presented some beautiful data with IDH inhibitors and intensive chemotherapy, immunotherapy.

This is really the cornerstone, I think, of where we’re going to go in the future. And I think obviously this as a target, as well as particularly other BCL2-related targets could also be interesting, particularly in myelofibrosis. I think we’re really going to see a lot, and especially the possibility of combining it with oral inhibitors such as aza, oral aza, to give a noninjectable chemotherapy option for patients, I think is really going to be a great step forward.

DR LOVE: Andrew, a question from the chatroom, do you think aza/ven will “cure” patients? And also any comments on your VIALE-C trial?

DR WEI: Yeah, so in terms of cure, I think that’s a more difficult question. We still have patients who were from the Phase I who relapsed sometimes 4, 5 years after being in remission. And so I think Mark alluded to the possibility that residual clones, even though they might be preleukemic, could be reservoirs for future transformation that we may need to consider how to deal with that. And so this concept of maintenance therapy is certainly going to be one for the future.

With respect to low-dose ara-C, we have really interesting data in patients with NPM1-mutant AML that this is incredibly effective. Most patients go into remission. Many patients eliminate the NPM1 MRD for years. And in fact, we’ve even seen patients relapse with NPM1-negative AML down the track, suggesting that we did take care of that clone very well. But again, are there reservoirs of residual progenitors which might bring the disease back?

And so I think the key question with both of the regimens, from VIALE-A and VIALE-C, is what do we do. Do we give treatment until remission, switch over to something that’s targetable? Continue until progression? Or look at a treatment-free interval to try and avoid inducing, I guess, targetable resistance. So I think these are fascinating questions for the future.

DR LOVE: So Mark, the other topic that you covered in your presentation is maintenance therapy. Maybe you can comment on this painting.

DR LEVIS: Well, the guy looks like Charlie Schiffer, and actually I took that photo, but I actually can’t remember what museum it’s at.

DR WEI: Who’s skull is it?

DR LEVIS: I don’t know. He’s pondering eternity.

DR LOVE: Pondering maintenance. Okay.

DR LEVIS: He’s pondering maintenance, yes.

DR LOVE: What is he thinking about?

DR LEVIS: Well, he’s come to this conclusion, and this was from a review article from a few years ago, but I think it actually turns out to be correct. Maintenance therapy in AML, in the normal setting, now Sasha and I and people, we use FLT3 inhibitors after patients have relapsed after transplant because it seems to help. But in general if therapy is incomplete, you better give maintenance. Of course that’s the case. But the maintenance trial that made the big splash last year at ASH was of course the one demonstrating the benefit of this drug, oral azacitidine.

And the point here was that, and Andrew can comment on this because he put some patients on this thing, the patients who went on this study did not get complete therapy, okay? Complete therapy meaning intensive induction and 3 or 4 cycles of consolidation or a transplant. No. They got 1 or 2 cycles and said I quit. Okay. Under that circumstance, those authors had mentioned, that’s when you really need a maintenance therapy. So was this effective therapy? Yes, beautiful study. Do these patients exist? Yes, they do, where you give them intensive therapy, and the poor patient falls apart and says I surrender. Okay, well we’ve got a treatment for you, this maintenance therapy. But again, it really isn’t quite the same as I’ve done all my therapy, I’ve done 7 + 3, and 3 cycles of HiDAC, now I’m going to give you this. I don’t think that this agent is going to be effective for that population.

DR LOVE: So Sasha, any comments about this study and where you see things heading in terms of maintenance therapy in this situation?

DR PERL: I recently had the same discussion with a patient after a cycle or 2 of consolidation, somebody who was over the age of 60, had an NPM1-mutated leukemia, did not have other high-risk genetic markers, and her question was is it okay to stop? Should I just go that oral azacitidine? And I said I think you need to finish all your therapy. Because I think at the end of the day, if you’re going to give curative therapy, you want to give curative therapy.

That being said, if you cannot get through all the intended therapy, I think the study clearly shows there’s a benefit to getting oral azacitidine. The disease protection is better than not giving anything. And the interesting thing to me, actually, is after people progress their survival is actually surprisingly long. The median duration of remission from study entry until progression, to memory, was about 10 months, but the median survival was 24 months. That’s actually a very long time after relapse.

I’m curious about that, and I don’t know if Andrew can comment on why that happened. But I think defining what is the population to give this drug to is a little bit challenging, and if you look at the label it’s a little bit vague there in terms of saying who should you give this to. I think we have trouble saying this is where the drug should be used based on the study findings when we take it into practice. But I think it’s as Mark said, if you literally can’t get through the therapy that you would give to really give the patient what you think is curative therapy, this is the drug for you, and it clearly works.

DR LOVE: Go ahead, Andrew.

DR WEI: There’s a couple of abstracts which might be of interest this year at ASH, where one is one presented Gail Roboz where patients with MRD, which was present in almost 50% of patients going onto the maintenance study that had flow-detected MRD, and the response rate and the survival was superior with respect to CC-486 regardless of MRD positivity or not.

There’s also another abstract where patients were compared whether they had 0, 1, 2, or more consolidation cycles of therapy. And interestingly the patients in the no consolidation group getting CC-486 actually did as well, if not better, than any of the placebo arms, regardless of the number of consolidation cycles. And if you had 2 or more consolidation cycles, and you got CC-486 afterwards, that was the population that did the best. So there’re definitely patients that just really fall apart after 1 or 2 cycles of chemotherapy, where this is definitely a useful treatment going forward.

DR LOVE: So one of the points, Dan, that was brought up by Mark and his concluding slide, and we already alluded to it, but I’m curious what your thoughts are as to at what point we might be able to go to an all-oral regimen of venetoclax and azacitidine with oral azacitidine. And what kind of data and how much data you would need to see, Dan, in order to make that move?

DR POLLYEA: Oh boy. I mean I think we’re all real keen to do this. And I think we have our thoughts, and probably regulatory agencies have others. I know a little bit of an easier question would be decitabine because that’s a treatment where the oral formulation has been deemed equivalent, bioequivalent, PK equivalent, and approved.

So oral azacitidine is a different situation. It doesn’t have that level of data, and although it’s the same chemical compound the PK properties are likely different. And the extent to which azacitidine is effective because of its PK properties you would have to be operating with great caution to just switch out oral azacitidine. But I think that that’s not the case for oral decitabine, and I think there are some studies underway looking at that.

And yes, as was said before, we’re all very excited about the prospect of a patient coming in with a newly diagnosed AML and handing them a handful of pills and telling them go home and we’ll see you in a couple days. I think that that future is very tantalizing.

DR LOVE: And certainly more of interest now with COVID going on and trying to keep people away from infusions, if possible. Andrew, I see that Patrick in the chatroom brought up the issue of CC-486 for MRD-positive patients after consolidation. Can you comment on how you answered?

DR WEI: Yeah, so as I mentioned, there’s an abstract this year showing that patients who are MRD positive, defined by a 0.1% flow MRD positivity, that is present in 50% of patients post chemotherapy. The study looked at patients with respect to relapse free and overall survival, whether they got CC-486 or not, and in both groups they actually did better, which is interesting because previous studies done by the MRC using injectable azacitidine showed that those with MRD positivity didn’t benefit, whereas those without did. And so I think that sets up really interesting trials in the future of how can we improve outcomes in MRD-positive patients using perhaps CC-486 as a backbone.

DR LOVE: So let’s finish out this segment by asking Mark to comment on one of the cases he presented in his presentation of a 70-year-old man with a complex karyotype and TP53 mutation.

DR LEVIS: Oh yeah. This was one of the earlier patients I treated with this combination. And when I met him, and he had the usual story, it always seems to hit when you retire, I guess. We better not retire. Something bad will happen to you. Anyway, the karyotype came back, this horrific long line of everything awful, along with the expected TP53. And I said you look thoroughly fit, but in fact I’ve never seen this disease cured in somebody like you. He was fit enough to get intensive therapy, be very clear, but I have never seen it do any good for this sort of patient.

And so I said well, we’ve got this new stuff here that looks intriguing. And this guy, other than he got briefly admitted because we were worried about tumor lysis, which happens once in a blue moon. It does happen. But it was just very striking that in red here you see his hemoglobin. This guy was hiking in Colorado, which is how he noticed. That’s how fit the guy was.

So his hemoglobin on this regimen just kind of merrily rockets back up. The platelet count, neutrophil count, everything. So literally within 70 days this man essentially has normal counts. And I said dude, you’re not going to be cured. And in fact he had obviously MRD. We could still detect the TP53 at 1%. I said dude, this is coming back. You have I don’t know how long.

He got his boat out and sailed that around all over the place, literally not needing to come to clinic. And he came in every 6 weeks to get the subcutaneous version of this and had a great year. Relapsed, I don’t know what cycle, at 12 months and died right at the median. There it is 18 months. But this is treating the disease not as AML, we have to try and cure everybody, but as liquid pancreatic cancer. My job is to try and give you quality of life and length of life. This is, again, even for the patients that we’re not curing, this is a dramatic improvement for the field.

DR LOVE: Sasha, any comments?

DR PERL: Yeah, I want to comment on that. Mark’s seen the slide that I give. I have a picture of a patient of mine out fishing, wearing a big hat and stuff.

DR LEVIS: I have.

DR PERL: And the title of the slide is this is what it looks like to take a FLT3 inhibitor. And it was just trying to prove the point that one of the successes of the ADMIRAL study was not just that the drug outperforms standard chemotherapy, but that the experience with it was very different than traditional chemotherapy. My patients took this as a pill once a day and got on with their lives and were able to do things they otherwise have been able to do. And that in and of itself I think is a success.

DR LOVE: So Mark, let’s finish out with your 73-year-old man. What happened with him?

DR LEVIS: Oh this guy has been my patient forever. MDS, a disease that’s horrifically uncurable for this guy. Okay, and he’s got nothing obviously targetable. Look at that, STAG2, TET2, NRAS, AML out of MDS. Give him aza/ven, and he flies into remission. And I brought up the possibility of transplant, and he said no, no, no. Tut tut. I’ve got a company to run, and off he ran.

And we checked his marrow a few months later. I said dude your mutations are inching back. I can do it if you like. So yes, he agreed. I used his grandson, peripheral blood stem cells from grandson. And he engrafted, and he went right back to work. And unfortunately in like April of this year, in the middle of COVID, okay, his counts are starting to drop again. We do a marrow. The exact same stupid mutations are there, okay? Again, we didn’t cure a darn thing. Everything worked perfectly.

All right. And he’s getting a little fed up with me at this point. He’s 78 now. And yes, I give him azacitidine. That’s well established. We have data that you can push somebody’s chimerism back with subq aza. And he says look, is there a pill? I hear there’s a pill. Can I have a pill? Okay, we got a pill.

And so in fact, yes, he’s on the pill. Actually, I have counts from him. They’re great. His counts have come back up. His platelets have come back up. He hasn’t been admitted. He hasn’t been transfused. Yeah, I’m going to leave him on oral azacitidine now. And here’s the latest toy that we have. I don’t even know if that’s on label. I’m not really sure.

He got that drug like 1 week after its approval, I think. He has like the world’s best insurance. They’ll just wave anything through.

Other Novel Agents and Investigational Strategies for Patients with AML

DR LOVE: All right. Well let’s finish out with Dan’s segment and his presentation on novel agents and new strategies in AML. And I guess one thing I want to begin with here, Dan, is the issue of secondary AML because obviously one of the things we want to talk about here is CPX-351.

DR POLLYEA: Yeah, thanks. It’s good to be the cleanup hitter here, take care of all the wastebasket stuff. All the stuff that we have in AML that we didn’t have time to talk about. Isn’t that a great development?

So it’s really important to know and understand the definition of secondary AML. It used to be because of its prognostic significance, but now there’s a therapeutic angle. So just so everyone’s on the same page what we’re talking about here is really 2 different things that have been lumped together. It’s AML from an antecedent hematologic disorder, usually that’s MDS, but it could be from an MPN or even other nonmalignant antecedent hematologic disorders like aplastic anemia. But it also lumps in treatment-related AML, which you can see the WHO definition there. So it’s really these 2 entities together.

And we all know that it’s a significant prognostic subgroup of patients. These are usually older patients. They have worse disease biology. They are less responsive to conventional treatments, worse overall survival, and really felt to be incurable without a stem cell transplant. And so this is why there’s a therapeutic angle to this. We know that CPX-351, the liposomal form of 7 + 3, daunorubicin and cytarabine in a fixed molar ratio, was given to patients with the designation of secondary AML in its own prospective clinical trial. These were all patients who were newly diagnosed, fit for induction with that definition that I gave you before of secondary AML and randomized to receive the CPX-351 versus 7 + 3.

And you can see that there was a survival benefit, 10 months versus 6 months, essentially, in this subgroup of patients. And that was statistically significant. And then also intriguingly, on the other survival curve, shows what happened to both of those patients, most of whom achieved a remission and then went to a transplant. And you can see a quite compelling survival for the CPX-351 patients who went to a transplant.

So I think that this is now an approved therapy, and it should be the standard of care for an induction-eligible secondary AML population. And particularly keep this in mind if this patient looks to be suitable for a transplant.

With respect to how do you define secondary AML, if you’ve been treating the patient for MDS, then you know. If you know that they came from your oncology colleague for their sarcoma or breast cancer, you know that they have a treatment-related AML. But you don’t always know if someone had a silent MDS that evolved to AML. We can tell that now based on the genomic signature, for the most part. That takes a little bit of time to come back. But if you want to wait for that information, if you feel it’s safe, there’s now data from the German group published in Blood, that waiting up to 2 weeks, maybe even more, for those results to come back to make a treatment decision didn’t have a negative impact on patient outcome. So something to keep in mind there.

DR LOVE: So before I ask Eytan for his comments on the biology and pharmacology of these observations and what’s going on, I just want to come back to you, Dan, with a common question we hear about the patient who develops AML while receiving HMA for MDS, and older patient. Do you keep the HMA going and add venetoclax? Do you use venetoclax alone? Or do you not use that strategy?

DR POLLYEA: Yeah, personally in that situation I like to add venetoclax to the HMA that they’re on. I have a variety of reasons for liking to do that, and there’s some data to support that in patients who fail an HMA but stay below the AML threshold and still have MDS.

But this is a situation that’s tailor-made for the LoDAC plus venetoclax subgroup because those patients, about a third of the patients on the VIALE-C study that Andrew wrote, had that scenario. And you can look at those outcomes and have reasonable expectations about how they’ll do. For me, I don’t switch to a different therapy at that point. That would certainly be an appropriate situation for CPX-351 in the right situation. And so that’s an option to consider too.

DR LOVE: So Eytan, any comments on CPX? You see a hazard rate of 0.46 on survival. What’s going on here, and your thought pharmacologically? Is this just an empiric observation, or any biology and pharmacology that explains it to you, Eytan?

DR STEIN: So CPX-351 is 7 + 3 in this liposome, which I don’t really know what a liposome is. I think of it as a soap bubble. So they put 7 + 3 into a soap bubble. And the data anecdotally, from the patients I’ve treated with this, is that number 1 I think the active agents are staying and getting into the bone marrow more effectively and perhaps having more potency when they’re actually in the bone marrow. But also I think that this agent isn’t ripping up peoples’ gastrointestinal tracts the way that standard 7 + 3 does. And that would suggest that those patients, even though they have, by the way, a prolonged duration of neutropenia, they don’t have a higher rate of death, suggesting that there’s something going on in terms of the safety that may be related to that.

DR LOVE: I’ve heard people talking about using it outpatient. Of course a big push toward outpatient, particularly earlier this year. Any thoughts about that, Eytan?

DR STEIN: Yeah, so we do that. So we do that. So there’s 2 reasons people do that. So one is that sometimes it’s not actually on the hospital formulary, and you actually have to give it in the outpatient setting. But we found because it’s given — 7 + 3, it’s continuous infusion of cytarabine. You can’t do it outpatient. But this is given on days 1, 3, and 5 as just a single infusion, so really is ripe for outpatient administration as long as you’re watching the patient very, very closely for the complications that ensue from all chemotherapy.

DR LOVE: So coming back to you, Dan, your comments on gemtuzumab and where we’re heading in terms of antibody-drug conjugates in AML.

DR POLLYEA: Yeah, gemtuzumab’s a drug that’s been around for a long time, has had kind of a mixed picture in our field. It is an antibody-drug conjugate targeting CD33, which most leukemic blasts express. I think the way we’ve settled on mostly using it is to consider it in the up-front treatment setting in a patient who’s getting induction chemotherapy and has a core binding factor abnormality. There’s a meta-analysis from I think 2015, which is really rare in AML to have a meta-analysis, but that’s the level of data we have. And there’s a very nice survival benefit in that population.

There is also survival benefit in the intermediate-risk group, less so, but you could certainly justify using it. Adverse-risk patients in this situation, no benefit. And there is some toxicity, so it really shouldn’t be used there.

DR LOVE: Mark —

DR LEVIS: I love using that for cytoreduction. It is a tiny bag. You can get it quick. And it’s a lot better than leukapheresis, which I’ve concluded I hate.

DR LOVE: What do you think about that, Dan?

DR LEVIS: And it’s on label, by the way. You can use this drug any way you want.

DR POLLYEA: All you need is CD33 expression. It’s a very flexible label. I’ve never thought about that. I would never say anything. All of Mark’s ideas are brilliant.

DR LEVIS: It was done out of desperation.

DR POLLYEA: You don’t have to put in a large-bore catheter —

DR LEVIS: No. That’s the point. You don’t have to phorese. It’s small volume. I don’t know what to do in those circumstances. And our patients were doing so poorly.

DR POLLYEA: Works great in APL too.

DR LEVIS: Well there is what gave me the inspiration.

DR POLLYEA: Yeah, so not much relapsed APL around anymore with these great up-front treatments, but if you do have that.

DR LEVIS: No, but I mean if you’ve got high-risk APL, high white count, a FLT3 or a white count of 50,000, and they’re like death, give GO to them. It just melts away. And that’s published. Those are reasonable use. But that kind of what gave me the idea, why am I not doing this. Why am I hammering these people with hydroxyurea?

DR LOVE: So Dan, you also in your talk talked about other antibody-drug conjugates. It seems like we’re seeing them all the time. There’s now one approved in bladder cancer, believe it or not.

DR POLLYEA: Oh, wow.

DR LOVE: What about in AML? Do any of these look exciting to you, Dan?

DR POLLYEA: I don’t know. I’m know this is the topic I was assigned, but I don’t know that this is the future. I think it’s challenging in AML. It’s not like these other diseases that have real logical targets that can be exploited in the form of a CAR T or an antibody. Maybe it’s out there. I’m not so enthusiastic.

DR LOVE: How about checkpoint inhibitors? Have they got you more excited?

DR POLLYEA: Yeah, I mean I have a little bit of the same feeling. I know that this is revolutionized a lot of solid tumors. Several of my colleagues are doing great work with these drugs. I sure hope they’re really effective. They certainly have a unique toxicity profile. Is this going to respond the same way as solid tumors, which like Mark pointed out, have dozens and dozens of mutations. AML is a disease with 3 to 5 mutations. Is the immunogenicity going to be the same when you try to get the body to recognize this and help your immune system destroy it? I think it’s going to be different, and I would love if this worked, but I’m not sure that this is what I would bet on.

DR LOVE: So before we go on, I’ve got to ask you all about, I’m not sure I can pronounce it, but it was the APR-246, I think eprenetapopt is the best I can do. But all I know is that’s what you guys were talking about prior to our discussion here. So Sasha, any thoughts about this very interesting and unique agent?

DR PERL: Very interesting.

DR LOVE: We’re going to see some data on it at ASH.

DR PERL: Very interesting drug. We’re most interested because it is specifically being developed in the worst of the worst patients with p53 mutations in AML who often have a very poor outcome, not because we can’t get responses. They get CRs about half the time with either intensive chemotherapy or venetoclax/HMA. But they don’t stay in response. And if you transplant them, they have a high relapse rate. And this is a very promising drug, both in MDS with p53 mutations, a very high response rate, and what seems to be some durability of response, and also in AML with that genotype.

The mechanism of action is purported to be a refolding of the protein leading to enhanced activity. We’ll see whether that is indeed the case in terms of correlative studies. But I think most people are excited to see something exciting is happening for p53-mutated patients, who are very hard to treat.

The other drug to look at in this setting is magrolimab, the antibody targeting CD47, which has had activity here, and again is also being targeted for drug approvals in the p53-mutant population.

DR LOVE: So Mark, I was asking you to explain to me how this new drug works, and also curious for your thoughts about this agent, pracinostat, which I guess based on, again press releases, not really showing very much.

But what about this new p53 agent, Mark, like what is it? You told me it was a small molecule. What does it do? And any thoughts about this PRAN-16-52 trial?

DR LEVIS: I’m not real excited about the PRAN, pracinostat. But I am intrigued by APR-246 because I’ve seen it work, and the rumors are they’ve already gone to the FDA at least with initial response data. And I’m not involved directly in it, so I can tell you whatever rumors I hear. However, it is a small molecule, but it is not binding to any active site. So it is a reducing agent.

And so it reputedly, and I’m sure it does bind to cystine residues, which are found in proteins, and should be reduced intracellularly. Yes, that will affect protein confirmation. I really wonder if it is working on almost to refold lots of protein. So you might say maybe it doesn’t need to work on just TP53, any misfolded protein, which might well have antileukemic activity. It clearly does because APR-246, when you gave it as a single agent, could induce remissions in a number of these patients. They always did a marrow after you gave the first infusion before starting azacitidine.

So the drug is active. It’s one of those things. Oh, we’re not really sure. But remember, no one’s absolutely certain how these darn hypomethylating agents work either.

DR LOVE: Well if you don’t know how it works. Andrew?

DR WEI: I’ll mention 1 thing about the pracinostat drug. Although it didn’t succeed in the Phase III in combination with azacitidine, we’re actually doing a trial of low-dose ara-C plus venetoclax plus pracinostat. And the reason for that was that - HDAC inhibitors plus targeted BCL2 were incredibly synergistic and incredibly synergistic in the absence of p53. And so that inspired us to take the triple combination forward into patients with adverse cytogenetic risk. And clearly I can’t say anything about the results, but watch this space.

DR LOVE: Yeah, I see a little smile on your face that encourages me. But anyhow, we’ll have to wait, I guess. And I want to thank the faculty so much for working with us.