Introduction

DR ERBA: Welcome. It’s great to be together here in Atlanta for this year’s ASH meeting and at this satellite symposium that’s being put on by Research To Practice. I think we’re going to have fun tonight. Rich and I actually did a similar program at the Pan Pacific meeting in August. I remember complaining a little bit to Neil Love that my picture wasn’t on the advertisement for the program. But they got one of me. And I’m just making clearly a very important point here. But then they found a picture of Rich with the usual look he gives me when I think I’ve just said something really brilliant. They captured the — yeah, exactly. There it is. Okay. You’re going to see that a lot tonight. Wait for it.

So tonight we’re going to be talking about what clinicians want to know. This is the 7th program that Research To Practice has put on in the last week, 3 at the San Antonio Breast meetings and 4 just today. We are at the end of that. And we are going to be discussing and addressing current questions and controversies in the management of acute myeloid leukemia and the myelodysplastic syndromes.

Here’s our faculty. Alice Mims from The Ohio State Comprehensive Cancer Center. Alexander Sasha Perl from the University of Pennsylvania. Rich Stone from the Dana-Farber Cancer Institute. Geoff Uy from Washington University School of Medicine. And I’m your moderator, Harry Erba from Duke University.

Wow. We flashed through those quickly. There were 34 medical oncologists, most of them community, some academic, who actually submitted their own cases. And so this is going to be fun for us because this is what leukemia docs do on a daily basis. It comes in text messages, it comes in pages, it comes on phone calls, emails with the questions that are coming from the community about how to manage acute myeloid leukemia and myelodysplastic syndrome. And that’s really what we’re going to try to do here. And I’ll move on. I think I moved on. Okay.

There they are. Okay. So download the RTP Live app on your smart phone or tablet to access the program information including the slides being presented during the program.

And we encourage clinicians in practice to submit questions. Feel free to submit the questions now before the program begins and throughout the program and if we have time, we will get to as many of those questions as we can, but we are on a tight timeline.

This is a live meeting, but it is being video and audio recorded. The proceedings from today will be edited and developed into an enduring web-based video/PowerPoint program. An email will be sent to all of the attendees when the activity is available. And to learn more about our educational programs, visit our website, www.ResearchToPractice.com. I just have to say that Neil Love has done an outstanding job over the years educating all of us on the everchanging landscape in medical oncology and we are truly indebted to him.

So we’re going to start tonight, What Clinicians Want to Know in AML and MDS. We have 5 modules starting with frontline treatment for patients with newly diagnosed AML ineligible for intensive therapy. We will move on to module 2, induction and maintenance therapy options for younger patients with AML with no targetable mutations. Module 3, optimal treatment approaches for AML with targetable mutations. Module 4, management of secondary acute myeloid leukemia. And then I will finish it out with current and future management approaches for the myelodysplastic syndromes.

And with that, we’re going to get started with the first module. So I’m going to ask Sasha to take the podium over there on the — to my left, your right I guess.

Front-Line Treatment for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Therapy

DR ERBA: And we’re going to start with the first of our cases which will be discussed by Alice Mims. So we’ll roll the video.

DR LOVE: Good evening everyone. I’m Neil Love from Research To Practice in our Real-World Virtual Case Library. The first patient is from the practice of Dr Eric Rupard. A very elderly man with a history of polycythemia vera who had a bone marrow biopsy because of progressive cytopenias and was found to have AML.

DR RUPARD: This is an 89-year-old white man with polycythemia vera for probably 20+ years. We started him on azacitidine/venetoclax and he had an almost immediate clinical response. He felt better rapidly. And within a couple of weeks, his hemoglobin started to rise and he’s now no longer transfusion-dependent, and day 21 bone marrow was a partial response. How do you approach the elderly patient with an acute myeloid leukemia, particularly this gentleman who’s almost 90? Do you approach the JAK2-positive PCV patient who develops acute myeloid leukemia as a consequence of that disease differently than you approach the patient who has a de novo AML?

DR SHARMA: Patients tolerate HMA/venetoclax much better than cytotoxic chemotherapy. We also frequently get AML patients who are in their 60’s, you know, late 60’s. They are fit, otherwise healthy. Based on the label, they would get intensive chemotherapy, but is it time to switch these patients to HMA/venetoclax therapy and take them to transplant? For instance, 68-year-old patient who has diabetes and coronary artery disease, but physically fit who got diagnosed with AML. Would you do 7+3 and take them to transplant? Or would you do azacitidine/venetoclax and take them to transplant?

DR COOK: HMAs and venetoclax we’re using very frequently. We are inconsistent at our center as to whether we hospitalize people or not. In recent months with all of the stress on hospital systems, we’ve been doing our best to not admit people that didn’t absolutely have to be admitted. And if you do keep people on the outpatient side, are you checking them more than once a day during their initial treatment course?

DR HALPERN: Are you doing less induction therapy because of COVID? And has this pushed you more towards HMA/venetoclax? Or was the field going that way anyway? I find venetoclax quite challenging to manage, and especially use with antifungals.

DR ERBA: Alice?

DR MIMS: I think that those are a lot of great questions and a lot of controversial topics as far as where we are with AML. And so for the first about approaching HMA/venetoclax in older versus the very old, I think from my standpoint, a lot of the discussion is based off of patient’s goals and then also looking at genomic features of their disease. Because I would say if a patient presented with an IDH mutation who was 89, 90, I might be more inclined to treat them with an IDH inhibitor as opposed to HMA/ven just because of some of the toxicities, myelosuppression. But I do think that that’s still an appropriate treatment for patients as long as they know risks and benefits and they want to pursue treatment. And for patients who have myeloproliferative disorder that transforms into an AML, what I would say for that is that I don’t necessarily treat those patients differently except for in the fact of having a discussion with them about their disease. It’s higher risk, it can be harder to get into remission, higher risk of relapse if they do respond and really thinking about transplant if they are potential candidates.

And for patients — the big question in regards to older patients and if they’re fit which is a relative term, but if they have the option of intensive chemotherapy versus venetoclax and HMA therapy, I think that question still remains to be answered. And I think there are studies that are going to be ongoing trying to answer that, even for younger patient populations, and to try to better determine in different genomic subsets what the better approach may be and try and determine that decision.

And for hospitalizing HMA/venetoclax patients, so we do both in our practice. We do have the capability to check labs twice a day in the outpatient setting. But there are patients who don’t have the ability to transfer back and forth, they may not have a social support and so we do admit some patients if we think that they need monitoring during their venetoclax ramp up.

And then lastly, the COVID question. So I would say that COVID has really made us think about patients a bit differently. It helps you to have that conversation about risks and benefits even more so and really counsel patients about trying to stay safe and be in appropriate environments. But I would say for the most part, for younger patients, I want to give them the therapy that we think is going to be most likely to have a good response and so we try not to shy away from that.

DR ERBA: And Dr Halpern made a comment at the end of all that, Alice, of the challenge of managing the myelosuppression, the challenge of the drug-drug interactions. I think we’ve all seen that. The package insert prescribing information gives us great guidance on what to do with venetoclax dosing. So we really need to pay attention to that because you could get into trouble pretty quickly. And then how we handle the myelosuppression that we see, basically, what I do is with each cycle, if it’s prolonged myelosuppression, I cut down the number of days in the next cycle. What do you think?

DR MIMS: Yeah. I agree. I think it’s important to make sure you do a bone marrow biopsy at the end of a cycle of treatment if patients don’t have evidence of circulating disease and then making your decisions based off of that. And then if they’re having prolonged suppression, I do more quickly go down to dose reductions, 21 days. And I’m more likely to use filgrastim and that type of supportive care in those scenarios.

DR ERBA: And that’s a very important point. Doing that bone marrow biopsy early, completely different than what we were telling them with HMAs alone. You have to wait 4, 5, 6 cycles, right? You have to do it in that first cycle and hold the drug until count recovery. Sasha, did you have anything?

DR PERL: Oh. I was just going to make the comment about growth factors. Once you know a patient is responding, it can be very helpful to speed up neutrophil recovery which is usually the limiting factor.

DR ERBA: Exactly. Geoff, the question I thought he was going to ask was, would you use a JAK2 inhibitor with aza/ven?

DR UY: I have not been using those sorts of things in my practice. I think for the case that was mentioned someone with prior P Vera, in the extremely elderly older adult population, a lot of times their AML doesn’t really behave much differently than their sort of accelerated phase MPM. So I really think it’s based on what their goals of care and what their symptomatology is. If they have constitutional symptoms, splenomegaly, sure, by all means, use a JAK inhibitor. But in general, I haven’t been too aggressive about giving very old patients chemotherapy.

DR ERBA: Yeah. And as you heard, this patient got better just with the aza/venetoclax, felt better right away. Let’s get to our polling questions. So here’s the first one. Without — regulatory and reimbursement issues aside, which initial treatment would you recommend for an older patient who is not eligible for intensive chemo who presents with AML and a FLT3-ITD? The choices are there for the sake of time, we’ll just show what people chose. And the most common choice was HMA plus venetoclax with a FLT3 inhibitor with HMA/venetoclax coming in second. Rich, would you like to make a comment about that?

DR STONE: Sure. I’m somewhat surprised by the number of people that have jumped to triplet therapy with only very minimal data in the published literature. I am medically conservative, although not politically I might add, and I would not do that at this point outside the context of a clinical trial. Based on the results of the LACEWING trial, I would probably give this — which were negative and based on the results of the VIALE-A trial which were positive, I would probably give this patient azacitidine plus venetoclax if they were unfit for intensive chemotherapy for I feel, at the moment at least, that’s the most appropriate therapy for all unfit adults with AML although Dr Perl may differ with me on that one.

DR PERL: I actually agree.

DR STONE: Oh good. I’d be more fun if you disagreed. But I think we don’t have the data that supports the use of early FLT3 inhibitor therapy in these patients.

DR ERBA: Yeah. The response rate is still very high and the durability of those responses is questioned. There was no survival benefit in that subset of patients who got aza with ven over aza alone. But we have to keep in mind the data of the combination with gilteritinib and venetoclax although very effective in getting deep remissions, also causes significant myelosuppression.

DR STONE: And hasn’t been used that much in upfront patients. Right, Sasha? Your data is in relapsed refractory?

DR PERL: Yeah. Correct. And I think my big concern in patients treated with HMA/ven who have FLT3 mutations, and particularly FLT3-ITD, is how long will it last because the durability may be the biggest issue there. And that’s the question is, so once you’re in response, do you stay with this? Do you change? Do you give a treatment break? And I don’t think we know the answer yet. But we need trials.

DR ERBA: Okay. Next question. Next polling question. Regulatory and reimbursement issues aside, which initial treatment would you recommend for an older patient who is not eligible for intensive chemo who presents with AML and an IDH1 mutation? And here’s a little bit more balance, but still a split between the doublets and the triplets. And the audience are going, this is sounding like myeloma all over again, God forbid. So, Geoff, what do you think?

DR UY: So I would pick other because I would give IV decitabine or azacitidine with venetoclax and not — I wouldn’t use the doublet with ivosidenib. I think that the response rates are roughly equivalent, but we know that ivosidenib can be potentially used in the salvage setting. So my preference is to save that for the second line setting. And oftentimes, we don’t know if they have an IDH1 or IDH2 at the initial presentation. So, in general, we start — my practice is I start HMA/venetoclax and then figure it out.

DR ERBA: I agree. And playing devil’s advocate, I’ll say though, is there a situation where I might even consider it? I think the data from MD Anderson on the triplet is interesting. It’s a little bit more myelosuppressive when you add the HMA in there. The venetoclax PK levels are different in the setting of ivosidenib, they’re a bit lower, but they showed very deep remissions. And so if you’re planning to get the patient to transplant, maybe that makes a difference, but we really don’t know.

DR UY: I think the one exception is for like patients who have significant comorbidities and I wouldn’t — I’m really thinking whether they deserve any, or should get any, chemotherapy. Those patients if they have an IDH1 inhibitor, I would consider ivosidenib alone.

DR ERBA: Yeah. And there’s data to support that. Okay. Well with that, let’s turn to Sasha — oh no. I’m sorry. Do you generally admit to the hospital all patients with AML who are receiving venetoclax in combination with HMA? Sasha? How do you handle that?

DR PERL: I don’t. I look at some of their risk factors for TLS. If they have preexisting renal dysfunction, if we had to cytoreduce them to get their white count down before starting, I would. But in many of the patients — for largely the reasons that were mentioned before, trying to not use the hospital resources and also make this easier on patients who have a relatively low risk of TLS.

DR ERBA: Yeah. I agree. They have to have a caregiver. They have to have, especially these older patients, have to have transportation to get in. You need to do it safely. They have to understand the dosing and all of that.

DR PERL: Right.

DR ERBA: But those are a select few patients. Definitely after cycle 1 once they’re in response, I think this is a regimen we can easily give in the outpatient setting.

DR PERL: Oh yeah.

DR ERBA: Sasha?

DR PERL: Okay. So I have been challenged to give a talk on frontline therapy for patients ineligible for intensive induction therapy. And I think with the conversation we just had, I can hopefully breeze through some of these slides relatively quickly here. I don’t need to introduce how hard it is to treat older patients, both because they have more comorbidity and also, no matter what you give them, they tend to do worse. The survival is worse in older patients. Then, also the risks of giving intensive therapy in older patients, some of which are listed here. Predict for induction mortality, ie, not making it out of the hospital. So if we can avoid that in patients who are likely to have complications, it’s always better. But the challenge has been, what are you going to do instead? So if we look, historically, the question was, what’s a reasonable non-intensive regimen? And I think over the years, really 2 drug singlets have emerged in terms of comparison arms for novel agents, either low-dose cytarabine or azacitidine, and these work about comparably well, even in a study that randomized patients to one or the other if appropriate. This is the AZA-AML-001 study where patients were randomized either to conventional care, whatever their physician thought was best for them, or azacitidine single agent. And patients were over the age of 65 with non-core binding factor AML and at least 30% blasts. And on this study, azacitidine and low-dose cytarabine performed about the same and actually not all that much differently from intensive chemotherapy in the patients fit enough to be treated with intensive therapy. So the question is, if you’re eligible for intensive therapy, should we be giving it in this age group?

And we now have more interesting data because we have more options. 4 drugs have been approved for AML since 2017. It’s really a different era. We no longer are stuck with just low-dose cytarabine or HMA as our low intensity option. There’s 4 new drugs that were specifically approved for patients ineligible for intensive therapy either alone or in combination which I’ve highlighted here in red. And I’m mostly going to talk about venetoclax combinations in this talk.

So just a very brief introduction of venetoclax. I think for anyone who treats CLL and has some familiarity in AML, you know this is a BCL2 antagonist. It induces apoptosis in cells by mimicking the effects of a BH3 protein, sticking to overexpressed BCL2, displacing proapoptotic proteins and insert into the mitochondrial membrane. And while in CLL, that in and of itself can treat the tumor, in AML you actually have to give this in combination. There’s relatively limited, if any, single agent activity, so best to combine rather than give as a single agent. And most of the data are with low-dose chemotherapy, i.e., HMA or low-dose cytarabine. The data were developed though single arm studies initially. 2 multi-center single arm studies were done either combining an HMA, either decitabine or azacitidine, with venetoclax or low-dose cytarabine. Mostly, the studies had similar eligibility and management principles. On these studies, every patient was hospitalized to mitigate against tumor lysis which wound up not being seen very frequently, if at all, when these criteria were met, i.e., a slow ramp up over a few days. And, obviously, that’s faster than in CLL, keeping the white count under 25 before initiation of the regimen. And patients on this study essentially were deemed ineligible based on either their age or the presence of comorbidities. That largely went along with the Ferrara criteria.

And the outcomes from the study showed a dramatically higher response rate in survival than what had been seen previously in low intensity therapy. These are the HMA data published in Blood about 2 years ago. CR and CRi rates of nearly 70%. A median overall survival of nearly 18 months. Considerably better than what had been seen on prior studies. And benefit was seen across many different subsets including older of the old, patients with comorbidities, secondary versus de novo, and various different cytogenetic abnormalities. And if we look at that study, you were not allowed to have a prior HMA, but the low-dose cytarabine study did include patients with prior MDS who’d had HMA therapy and they didn’t do quite as well as we saw with HMA plus ven in patients not treated with that therapy. But if we just look at the venetoclax and low-dose Ara-C in patients who had not been treated for MDS with an HMA, they actually look fairly similar to the HMA plus ven data I just showed you, CR/CRi rates of 62%. Median overall survival of about 14 months. Again, looks better than single agent low-dose chemotherapy. And this was once daily Ara-C, so something that you could do at home once you were on therapy relatively straightforward.

Toxicity management. We talked a little bit about this. Patients really do best when they’re monitored closely on this regimen. It is not a set it and forget it kind of therapy. You do need to watch these patients closely by checking the marrow about a month in. I actually check about 3 weeks in. And hold drugs if patients have a morphologic leukemia free state. And patients can take a few cycles to respond, but it’s not uncommon to see a CR or a CRi or at least a morphologic leukemia free state within a single cycle in these patients. And while tumor lysis syndrome was not seen on the trials, it’s not to say it doesn’t happen. So in higher risk patients, I really do think it is necessary to admit them for close monitoring. And we’ve alluded to the dose modifications. And the proof is in the pudding when you take a regimen like this and do a randomized study and show that not only is it active and tolerable, but it beats effective — standard therapy to establish effectively a new standard of care. And that’s what the VIALE-A study did. A very important study published a year ago by Courtney DiNardo and colleagues.

This is the design of the study which I think should be familiar to you, giving venetoclax at a 400 mg dose for 28-day cycles with standard dose azacitidine and compared to azacitidine given with a placebo that was matching. Patients were randomized 2 to 1 to this study, enrolled over 400 patients. And the primary endpoint was overall survival. And as we see, the remission rates were considerably higher in the venetoclax arm — no, sorry. Oops. I can’t go backwards. All right. Remission rates were higher in the venetoclax arm and statistically significantly better as you can see here. And this was true across a number of mutational subtypes and cytogenetic abnormalities. But the patients who seemed to do the best on this were indeed the patients who had IDH mutations in terms of the relative benefits for the venetoclax arm. This was also true in terms of an overall survival benefit for the combination arm. And as you look at the subgroup analysis, again, the IDH mutated patients are highlighted there with the lowest hazard ratio for survival showing the greatest survival benefit of any subgroup. And so with these data, again, here highlighting the IDH mutated patients who saw the greatest benefit here. This effectively is like a targeted therapy for them based on some of the biology related to IDH mutation.

The VIALE-C study is a follow-up to that using the venetoclax plus low-dose cytarabine regimen. It was a smaller study. It was not actually powered adequately in final analysis to show the survival benefit seen on VIALE-A. And actually, at primary analysis, was not a significant improvement in survival, but with 6 months of further follow-up, that benefit was seen. And, again, better response rate and indeed better survival with longer follow-up on that study in the combination arm. So both of these are approved for patients.

And the ongoing questions are, we now know that there’s a new standard for patients who are deemed unfit for intensive induction, so how do we define that? And I’m not going to define that for you here. I’m going to raise the question of, does that really matter? If we have a new standard that’s better than azacitidine and azacitidine looked standard in terms of being comparable to almost any other therapy whether it was low-dose Ara-C, whether it was intensive therapy, this is potentially better than it. So the real question in the field right now is, shouldn’t we be giving this to everybody who isn’t getting intensive therapy with curative intent? And the other question is, if you do want to give curative intent, is this something that you can bridge to transplant?

Are there any data for somebody who might improve their performance status, might not be eligible for intensive therapy right off and later on does do so? Or is that even a preferred approach? What is second line therapy for these patients is still to be decided. But how do we combine these with other targeted agents is something that we’re starting to figure out now and they’ll be lots of data presented at this meeting as to triplet combinations. But right now, I don’t think that these are standard as mentioned before. With the question of should we use intensive induction versus venetoclax-based strategies? Just put side by side and recognizing the caveats of doing cross study comparisons. It just reminds you that the CPX versus 3+7 randomized study was in patients who were fit for induction chemotherapy and the response rate and the survival on this study, which was patients over the age of 60 who were deemed fit for induction chemotherapy, does not look to stand out to be appreciably better than ven/HMA. It actually looks a little bit inferior to my eyes recognizing those caveats. And recognize that one-third of patients on this study went to transplant. Less than 10%, about 10% of patients on the ven/HMA study did. So that benefit was not from transplant.

What if you do take patients to transplant after ven/HMA? These are data recently published from the University of Colorado group showing in patients over the age of 60 who were treated largely with venetoclax/HMA as the preferred regimen at that center and about half of them were referred for a transplant evaluation. The patients who did go on to transplant had quite good survival, so that is a reasonable option from these data, not something that we can show in multi-center studies, but something we’re actively looking at at our center as well. And I think the field is starting to look at this as a reasonable thing.

Lastly, if we can better figure out how people are responding, perhaps instead of treating patients until progression or intolerance, we can give a defined period of therapy and then stop and observe. And the patients with the best response, it’s no different than when we give 7+3 and 4 cycles of high-dose Ara-C in a younger patient. We can treat them with curative intent. And my hope would be that we don’t keep people indefinitely on this therapy who might only need a fixed duration like in CLL. The data I’m showing you here showed that about one-quarter of patients become MRD negative with this regimen and their outcome regardless of whether they became MRD negative after a single cycle or up to 7 cycles was overlapping in terms of their protection from relapse. So I’m going to zip through this slide and just go to the conclusions.

These doublets have opened up new treatment options that look to work better than existing therapy that was low intensity and may actually be at least as good, if not better than high intensity therapy for patients eligible for more intensive options. We need randomized studies to answer this. It’s a bit of a learning curve to give the regimen. We don’t have the data yet in fit patients as to what should be the frontline approach. And there is clinical equipoise about that and there are starting to be randomized studies answering that question in fit patients. And lastly, do think of this regimen for your IDH mutated patients. It can particularly help them. And I think MRD data are interesting, but I would not yet say that that’s standard to introduce this and use that for a fixed duration. It’s something being studied right now. Thanks for your attention.

DR ERBA: Thanks, Sasha. Okay. Let’s move on. We don’t have time for questions right now, but so I’ll ask Rich to take Sasha’s place at the podium. And let’s start the video.

Induction and Maintenance Therapy Options for Younger Patients with AML and No Targetable Mutations

DR LOVE: The next case is from the practice of Dr Rebecca Olin. A 43-year-old woman with AML and monocytic differentiation with a FLT TKD and NPM1 mutation.

DR OLIN: One question would be, sort of simple, but is midostaurin appropriate to be added to this therapy? Another question is whether this patient should receive an allogeneic transplant. In this case, because she is normal cytogenetics and NPM1-positive, she is considered good risk and, therefore, might be cured by chemotherapy consolidation alone. Would anybody do anything differently if this was a FLT3-ITD patient?

DR COOK: I’d be interested to hear how people are managing TP53-mutated disease. I feel like that’s a difficult disease to manage and would be interested in people’s input. Also how people are following molecular testing in that setting. Do people feel that it’s important to be seeing a decrease in the TP53 VAF? Is that part of how you do your disease evaluation to determine efficacy?

DR HALPERN: Gemtuzumab ozogamicin, how are people using it? Are they using it in all favorable-risk patients, or are they just using it in core-binding factor? Are they using it in intermediate-risk patients? Are they using a fractionated approach? Some people still have concern to use it in a patient who’s going into transplant because of the concerns for veno occlusive disease after transplant. Another question I have for them is, when we do have these patients with FLT3 and IDH mutations, potentially unfit for chemotherapy, and by whatever their definition is, are you starting with the inhibitor plus an HMA? Are you starting with venetoclax? Are you using the triplet therapies? And then when they fail the triplet therapies, what are you going to?

DR ERBA: Okay. Geoff?

DR UY: Okay. So a couple questions here. The first one is about FLT3-TKDs and NPM1 mutations. So FLT3 mutations come in 2 major flavors. The first is the more common ITD which is associated with increased risk of relapse, adverse prognosis. And then the TKD which is also an activating mutation, but doesn’t really carry the same adverse prognostic feature as the ITD. So for patients with an NPM1 which carries a favorable prognostic risk in the absence of an ITD, these are considered favorable-risk patients. These are patients who are thought to not benefit from transplant first remission. So we would tend to consolidate these patients with chemotherapy alone and not — and reserve transplant for the time of relapse.

The second question is a good one. And it’s a question that I have no idea how to answer. What to do with a patient with a P53 mutation. So we know that these are the worst actors of the AML bunch. They’re associated with resistance to chemotherapy, high rates of relapse, even with agents such as hypomethylating agents and venetoclax, the responses tend to be very short-lived. So the easy answer is I think that all these patients should be considered for clinical trials when available. I will say that it’s very controversial what to do with younger patients whether or not they should receive standard induction versus HMA/venetoclax and that’s the subject of a proposed clinical trial. For older adults, I will say that I am unenthusiastic about giving intensive chemotherapy and thus will favor more HMA/venetoclax approaches. Equally, unenthusiastic about transplanting older adults with P53 mutations because we know that the outcome is quite poor.

In terms of how we follow the variant allele fractions in P53, in many of these cases the variant allele fraction does go down and I think it is a little bit important to know what it is because the adverse prognostic features of TP53 aren’t uniform across the population. It seems to be more important in patients with biallelic mutations versus patients with maybe monoallelic mutations at low variant allele frequencies. And even patients who can have undetectable P53 VAFs, usually if you sequence deep enough or use more sensitive techniques, it’s still there somewhere.

The last question is about gemtuzumab ozogamicin which has really a storied history in AML. It initially received expediated approval and then was withdrawn from the market and then is back on the market again. And so, in general, the reapproval of gemtuzumab was based on a meta-analysis which showed improved survival and that improved survival was particularly notable in the patients with favorable-risk cytogenetics, those patients with core binding factor leukemias, inversion 16 and 8;21. There was a favorable benefit of gemtuzumab also in the intermediate-risk patient population, but was not as pronounced. And we also know that there’s a risk of gemtuzumab inducing veno-occlusive disease in patients who subsequently go to transplant.

So for those reasons, our practice is primarily to use gemtuzumab in the favorable-risk, the core binding factor leukemias only. We do not use it in the intermediate-risk because there are some patients within that group that we haven’t quite made the determination from just a practical standpoint whether or not they’re going to go on to transplant. We do use — I do use a fractionator approach in my practice. I usually give it, I think, it’s day 1, 4 and 7, 3 mg/m². And this is based on data that shows that just giving lower doses of gemtuzumab compared to the higher doses, you actually saturate all your C33 binding sites at the low doses and then after you give a dose, you rapidly re-express CD33 through receptor recycling. So the thought is that if you give several doses over a long — smaller doses over a longer period of time, you may potentiate some of the toxicity from the higher dose.

And then the last question is about FLT3 and IDH mutations. So as Sasha mentioned that these patients tend to respond pretty well to HMA plus venetoclax. So that is my current standard of care frontline treatment in that I reserve more targeted therapies for the time of relapse. I think there’s insufficient data at present to recommend the triplet therapy and we know that these can be potentially associated with more myelosuppression.

DR ERBA: Thanks, Geoff.

DR UY: For what?

DR ERBA: That was good.

DR UY: Okay.

DR ERBA: The German AML study group actually looked at GO in patients with nucleophosmin mutation, right? And they saw a worse event free survival because of early death.

DR UY: And then, but the meta-analysis was pretty neutral.

DR ERBA: Yeah.

DR UY: There’s not —

DR ERBA: But I agree with you, many of those patients may go on to transplant. And hopefully, there’ll be new options for those patients shortly. Okay. Why don’t we move on then to the questions? Which initial treatment would you recommend for a 65-year-old man with AML with performance status 1 and pancytopenia, 35% marrow? There they are. And the choice — the first one was HMA with venetoclax, followed closely by 7+3. Alice, what do you think?

DR MIMS: That’s a tough question. I think there’s more data coming out showing about less benefit for venetoclax for the TP53 complex karyotype and there will be some things presented at ASH. For me in particular, I think we’re starting to move towards giving single agent HMA therapy though you could still consider HMA plus ven. I would not give any of the oral HMA therapies at this time because I don’t think there’s enough data to support those in combination with venetoclax.

DR ERBA: And maybe the 15% who chose other was what Geoff said, and I think we all agree with, these patients need a clinical trial.

DR MIMS: Exactly. Yes.

DR ERBA: Some interesting agents coming along like the anti-CD47 drugs may have a particular benefit here, but we’ll need to see. Okay. And then the next question, Sasha, would you substitute — I think, wait a second, I think she already answered for you. Would you substitute CC-486 or cedazuridine/decitabine for standard administration of parenteral azacitidine or decitabine in combination with venetoclax?

DR PERL: Sorry. I think sort of as we’ve alluded to before, we want to see the data. There are studies that are just starting to go now showing mostly feasibility. We don’t have long-term data here. As far as we can tell, the oral decitabine is bioequivalent. If I were going to choose one of them, that would be the one I would choose.

DR ERBA: Yeah.

DR PERL: But I think we really don’t know at all how to give the oral azacitidine which is not bioequivalent and that has a significant GI toxicity too. So it might be a feasibility issue.

DR ERBA: Yeah.

DR PERL: The simple answer is I think I’d rather do that on a study unless there were extenuating circumstances that kept the patient from being able to come in.

DR ERBA: Yeah. Maybe once they were in remission, I might switch to oral cedazuridine/decitabine.

DR PERL: Literally fall away or something. Yeah.

DR ERBA: But I agree. Not CC-486. Rich, I’ll turn it over to you.

DR STONE: Thank you, Harry. I’m tasked with talking about induction and maintenance options for younger patients with AML and no targetable mutations which presumably means FLT3 mutations, no, and IDH mutations, no, although right now, we don’t have any standard therapy for IDH mutant patients anyway. So I’ll talk a little bit about the goals of therapy, the disease heterogeneity of AML which we’re all aware of, induction with venetoclax and a few notes about post-remission therapy.

So I think we all still believe that we have 2 dual goals in AML therapy. The first is to achieve complete remission with induction chemotherapy, at least in most younger adults. And we go from about 1012 cells to 109 cells which still is a sizeable though undetectable reservoir of leukemia which we must eradicate with additional therapy if cure is the goal, and it is for most younger patients. That additional therapy could take the form of allogeneic stem cell transplant, even autologous stem cell transplant or some form of chemotherapy consolidation and/or maintenance.

I’d also like to point out that CR also was not created equal amongst different patients. We care about deep complete remissions. That should be the goal because people will do better with their consolidation chemotherapy or their allogeneic stem cell transplant if they’ve achieved a very deep remission. And we now have ways to measure that. I’m not going to go over that tonight. But with flow cytometric or molecular genetic techniques, we can measure down to 1 in 104 cells as opposed to 1 in 100 cells or 1 in 20 cells with morphologic techniques.

So disease heterogeneity, it’s implicit in what we’ve been talking about tonight, but it’s very important to think about. And that indeed we all think about that very much when we see an AML patient, even a younger AML patient or maybe especially a younger AML patient. We think about whether they’re favorable-risk, intermediate-risk or poor-risk. And most of us use the ELN classification system which takes advantage of both cytogenetic and genetic data and puts it together. And the favorable-risk is mainly core binding factor 8;21 and inversion 16 cytogenetics, but also includes low FLT3 burden, NPM1 mutant patients. And the adverse cytogenetics you’re well aware of, bad karyotype, inversion chromosome 3 and other problems like that. And intermediate is most people that are in the middle.

So we have changed things to some of the new drugs that Sasha mentioned in the last few years how we approach the younger adult with AML. And you’ll hear more in a few minutes about FLT3 AML which is now — we now use a FLT3 inhibitor. The standard therapy, I think, is still daunorubicin and cytarabine, but there are many investigators that use FLAG-IDA upfront although that’s more toxic and the bridge didn’t show that it was clearly superior to a more traditional chemotherapy approach. Gemtuzumab, you just heard from a question from the oncologist about where we use that. I agree with what Geoff said about restricting it to use in core binding factor AML although the drug is approved for all types of AML and does have a benefit, as Geoff mentioned, in the intermediate-risk, but not used because of the fear of VOD after transplant in that group. CPX-351, Sasha mentioned that. That is approved in patients who have secondary AML, AML after prior MDS or prior chemotherapy or MDS related changes in their bone marrow. In terms of younger adults, it’s important to point out that the major study, or the study, that led to the approval of CPX-351 was done on people between 60 and 75 years of age. The FDA chose to approve it in all age groups if they had the same biology that I alluded to. So that’s just something to consider. I do use it in younger people, but we should be aware that there’s not a whole lot of data supporting that. And then I do use HMA/ven regimens in adverse risk younger adults. That maybe is a bridge too far. The standard of care remains 3 + 7.

So going over some of this data, as you can see from the bottom curve here, the monosomal karyotype, that means a person with a couple of monosomies or one monosomy and a balanced translocation, do miserably with our current therapy. So it’s hard for me to — and those are the TP53 patients by and large. So it’s hard for me to look at patients in the eye and say I’m going to give you 3+7 and make you sick as hell when it’s not going to help you. Maybe aza/ven is a way to get some place without making them terribly ill.

Now you saw this prototypic iconic slide describing the role — the mechanism of action of venetoclax and I won’t repeat it, but I will say that venetoclax is being used with increasing frequency, at least in clinical trials, for the younger adult with AML adding it to chemotherapy. What is the data supporting that? And I will say well the data that I’m about to show you is very exciting. I don’t think it’s ready for primetime yet. The US Intergroup will soon be doing a trial that will be comparing venetoclax/HMA to 3+7. There will also be a 3+7 and venetoclax arm in those trials. So I think that’s important to wait for this data, but the data that Dr DiNardo from MD Anderson has amassed with FLAG-IDA and venetoclax is impressive. This is her paper from the JCO published recently looking at mainly relapsed and refractory patients getting FLAG-IDA and venetoclax. But take a look at the newly diagnosed or ND AML, there are only 29 patients. She’s presenting a larger group of newly diagnosed patients to get FLAG-IDA/ven. A couple of points, notice that the Phase Ib dose of cytarabine was 2 g/m². They had to decrease it to 1.5 g/m² in the Phase II because the higher dose was too toxic. Same for the duration of venetoclax. I think most people would, who do this for a living, would probably say that the original venetoclax maybe was given too long a period of time and that’s certainly true in AML induction. But if we look at the data, if you look at the column the second from the left, Phase IIa newly diagnosed 26 patients, pretty high complete response rate, 97%. Almost all the patients were MRD negative. So very exciting regimen. The safety has to be confirmed outside of MD Anderson.

There have been other trials that have combined induction therapy with venetoclax, namely a paper from Australia, Andrew Wei and colleagues, called the CAVEAT trial in which they gave 5+2 plus venetoclax. The complete remission rate was high, 72%. I don’t know what a comparable complete remission rate would have been with 5+2 in a similar patient population. At Dana-Farber and at MD Anderson, we’ve been doing a trial where we’re combining 7+3 plus venetoclax. Again, complete remission rate very high and we’re excited about the high MRD negative rate, but we’ve had to reduce the dose of venetoclax in consolidation because it is a bit toxic. There’s also a paper with CIA therapy, I don’t want you to be suspicious of a paper with CIA in the title, plus venetoclax. And so they also had a very high complete remission rate. So I think there’ll be a lot more to say about induction with venetoclax.

In the post-remission, to make a long story short, we use high-dose Ara-C only in the CBF group. And in the NPM1 mutant/FLT3 wild type group, we use Ara-C, but Ara-C at a lower dose. It’s probably not necessary to use the full 3 g/m² dose. In adverse-risk, intermediate-risk, we do allogeneic stem cell transplants fairly routinely. We follow MRD. What to do about that is not really known. If you’re MRD negative, you’re great with chemo or transplant. If you’re MRD positive, you’re probably better off with transplant although the relapse rate with transplant is high. And now we can use oral azacitidine in older adults who are not going to go to transplant. This is the data supporting high-dose Ara-C. It dates to the mid-90’s now from Bob Mayer’s trial. It does not work in older adults. It works in younger adults. The people who benefit are those with CBF mutations and a lot of people forget about the paper that showed that RAS mutant patients benefit. So this is the data from a meta-analysis showing that people who have everything but favorable-risk chromosomes benefit from consolidation therapy in first remission.

Do we maintain people after allogeneic transplant? There’s a VIALE-T trial going on which is going to analyze venetoclax and azacitidine versus best supportive care as maintenance therapy for patients undergoing allogeneic stem cell transplant. Oral azacitidine, as was mentioned previously, is oral azacitidine, but with a pleiotropic mechanism of action and is not bioequivalent to IV azacitidine. So that has to be looked at separately. In the QUAZAR trial published by Andrew Wei in the New England Journal of Medicine last year was randomizing patients 55 years of age or older who were not going to have an allogeneic stem cell transplant, but who were treated with intensive chemotherapy to oral azacitidine or placebo. And there was an overall survival and relapse free survival benefit. So can we do better than oral azacitidine in this narrow group of patients who aren’t going to have transplants, but are treated with intensive chemotherapy? I don’t have too many patients like that in my practice, but anyway. In that group of patients, oral aza was clearly better than doing nothing or giving placebo. And so the VIALE-M trial will add venetoclax to oral azacitidine compared to oral azacitidine alone as maintenance therapy in a similar group of patients. I think that’s a completely rational and good idea.

So in conclusion, one induction size does not fit all. Induction goals should be the safe achievement of an MRD negative state. And the post-remission goal should be to eradicate all disease with an allogeneic transplant. And we’ll have to see if maintenance with oral azacitidine plus venetoclax makes sense in those people who aren’t going to have a transplant. And I’ll stop there. Thank you very much.

DR ERBA: Thanks, Rich.

DR STONE: Oh no. Hold your applause. Thank you.

DR ERBA: Why? Are you going to say something else? No. I think we’re done. We don’t have time for questions. Yes?

DR STONE: Questions? Sure.

DR ERBA: No. We don’t have time for questions.

DR STONE: Okay.

DR ERBA: So come on over here.

DR STONE: I’m supposed to go over there? I thought I was supposed to stay here for the rest of the time.

DR ERBA: No. No. No.

DR STONE: Oh no. That’s not true. You’re wrong.

DR ERBA: No because Alice wants to be 6 feet away from you.

DR STONE: Right. Okay. Well that’s —

DR ERBA: Thanks, Alice. Oh careful.

DR MIMS: I was warned about that.

DR ERBA: Okay. Let’s roll the video before Alice gets to her talk.

Optimal Treatment Approaches for AML with Targetable Mutations

DR LOVE: The next case is a patient of Dr Neil Morganstein. A 91-year-old woman who was recently treated unsuccessfully with azacitidine for high-risk MDS and shortly thereafter developed AML. After being counseled about available options, the patient elected to receive palliative care and shortly thereafter the NGS report came back noting an IDH1 mutation.

DR MORGANSTEIN: This is like a homerun. This doesn’t happen very often. She was on hospice at this time. We were able to get her expanded access ivosidenib. She recovered her white count, her hemoglobin, and her platelets went up to about 50 to 60,000. And she’s been maintained on ivosidenib now for 3 years, okay? Perfect quality of life. Perfect health. She’s incredible. Transfusion independent and has not had a single solitary side effect.

DR LOVE: You must really enjoy seeing her in the waiting room.

DR MORGANSTEIN: I love seeing her. She’s one of my favorites. She’s 91 now. But like one of these women who come into the office well made up, has her hair done, has her nails done. She looks fabulous.

DR LOVE: Any questions about IDH inhibitors?

DR COOK: I’d be interested how people are managing older adults, particularly who have any kinds of cardiopulmonary disease and you’re really worried that they won’t do well with differentiation syndrome. Are you prophylaxing at a set time? I’d also be interested, when you have people who have persistent disease on the IDH inhibitors, what are you doing after that? The other thing I have had come up quite a bit is when people’s bilirubin goes up on some of these therapies. How are you managing dose reductions? Are you just treating through?

DR SHARMA: We frequently encounter a situation where we have more than one targetable mutation. We get patients with FLT3-ITD with IDH1 or IDH2 mutation, for instance. Any tips for practicing hematologists like us in that regard?

DR ERBA: A lot of good questions. A great case. I agree. It brings up the question of patients on an HMA for MDS and then progresses to AML, what do you do? And I think the most important message there is you do targeted mutational analysis for FLT3 and for IDH because we have agents for those patients. But if you didn’t have a target, you could think about adding on venetoclax there or switching to low-dose cytarabine and venetoclax based on the VIALE-A trial showing about one-third of those patients would respond. And I bet you that patient would have responded with an IDH1 mutation there. But I applaud Neil for giving this patient ivosidenib in that situation. So well done. About 25% of patients who progressed from AML — MDS to AML have an IDH mutation, either 1 or 2.

Now the difficulty in managing patients with IDH inhibitors is the differentiation syndrome. And what distinguishes it from the situation APL is that in APL, you know when it’s going to happen, only during induction, usually within the first 2 to 3 weeks. The second thing is you have no doubt that that patient, if they survive differentiation syndrome, is going to achieve a remission. This is different here. Remember the response rates to the IDH inhibitors in the relapsed refractory setting are about 40% for enasidenib and about one-third of patients for ivosidenib. So even if a patient develops differentiation syndrome, it actually doesn’t predict for a response. Why might that be? Well I think one reason is it’s really, really tough to distinguish this pseudo proliferation, this leukocytosis that you can get with differentiation and with all of the things that go along with that like capillary leak, pulmonary infiltrates, fevers, hypoxia. It sounds like progression of disease with pneumonia or leukostasis. And I think sometimes we confuse these 2 things. So I don’t prophylax because I don’t know how to do this with an IDH inhibitor because I’d have patients on steroids for a very long time because this can happen any time in the first 4 months from supposedly day 1 which I never understood from the trials. But it can happen anytime. So you just have to be vigilant. You just need to watch these patients very closely and check in with them quite a bit.

In terms of persistent disease, it depends on the goal. If I have an older patient who’s not a transplant candidate, I don’t care how many blasts are in the marrow. I just want to see their blood counts get better. And these drugs can lead to differentiation and improvement in blood counts. And in fact, I don’t like sending marrows to the pathologist because they have a really tough time sometimes, especially early on, distinguishing active disease from differentiation. And we’re seeing that with other drugs that are coming along as well. So it depends. If it’s a patient that you’re trying to bridge to transplant, yeah, it’s going to be an issue and it brings up the question, how long do you keep a patient on an IDH inhibitor alone if the goal is to get them to transplant? I don’t think any of us really know the answer to that or how deep a remission you need to get. All I could tell you is we had patients in the Phase I studies that led to approval who did go to transplant and did well after transplant. But for the typical older patient, I try not to do bone marrow biopsies because as long as the blood counts are getting better, but every once in a while, I’ll do it just to say, oh look at that, it’s really great and then find out that the disease is still there and then I have to explain it. That’s tough.

How do I manage the hyperbilirubinemia? That happens with enasidenib. It’s an unconjugated hyperbilirubinemia. And basically, I approach it the same was as I do with nilotinib and hyperbilirubinemia, I ignore it. I hope that’s the right answer. It’s not the FDA approved answer by the way, but that’s okay.

And then finally, concomitant FLT3 in IDH mutations. The thing that we saw in the Phase I studies of the IDH inhibitors was quite consistent between enasidenib and ivosidenib and that was if you had many mutations, the response rates were lower, like more than 6. But specifically, if you had mutations in the receptor tyrosine kinase pathway including FLT3 or KIT or the RAS/MAP kinase pathway, so RAS mutations, those patients had a very low rate of response. And so when I face this situation, what I do is I start with a FLT3 inhibitor because that’s what’s driving the disease. These patients have, especially if it’s an ITD, will have a proliferative relapse of their disease and you need to get that under control. And then I think it’s a matter of a question, a good question, of whether you even have to add in the IDH inhibitor. I would look to see what’s going on with the disease after you get some kind of control of the disease with the FLT3 inhibitor. But, Sasha, I’d be very interested in your take on that. That’s my last point, so you can —

DR PERL: I’ve given both at the same time. It comes up. It doesn’t come up all that often. I think you’d mentioned that.

DR ERBA: Yeah.

DR PERL: But, yeah. I think we’ve all seen this, that patients who have proliferative disease just don’t have enough time to wait for that slow response to the IDH inhibitor.

DR ERBA: Yeah. I start with the FLT3 inhibitor because —

DR PERL: Yeah.

DR ERBA: With gilteritinib, you’ll see a very rapid reduction in peripheral blood counts and then you could add in the IDH inhibitor.

DR PERL: But even with gil, it takes a long time for the counts to improve even though the white count drops very fast.

DR ERBA: Well yeah. Yeah. But to control the disease, you can get them there. Okay. Let’s move on to our polling questions. What would you recommend as first line therapy to a 78-year-old patient who presents with intermediate-risk AML and a FLT3-ITD? I think we’ve kind of done these questions, but let’s move on. And it’s HMA/venetoclax. Geoff, what do you think?

DR UY: Yep. I agree.

DR ERBA: Okay. Good enough. I think we’ve done these. And this one as well. Same question with an IDH1 mutation. Let’s see what the audience said. And the audience said nothing. Oh HMA/ven. And then the question, again, about adding in the ivosidenib and we’ve discussed that quite a bit. So I think we can move on. Maybe we got ourselves a little bit more time now. And, Alice, you could take over.

DR MIMS: Okay. Well I’m excited to be here with y’all today to talk about the topic of approaching patients with AML with targetable mutations. And obviously, it’s a big area of controversy where clinical trials need to still move forward. And we’ve talked about it quite a bit in some of the questions that keep coming up, I think that’s a recurrent refrain. And so what I want to talk about is the just optimal approach for newly diagnosed or relapsed refractory patients with FLT3 mutations, IDH mutations, talk about data ongoing with current clinical trials with both FLT3 and IDH mutations, long-term data supporting the use of enasidenib in relapsed refractory IDH2 mutated disease and then also what do we think about for venetoclax-based therapy in patients with FLT3 or IDH1 or 2 mutations.

And so this is how I generally think about patients when I’m approaching them with FLT3 mutations. So I’ll talk about those patients first. And so for right now, FLT3-ITD, TKD, I kind of lumped those together in regards to picking a choice of therapy, not necessarily therapy choices later on. But with our current targeted therapies that are FDA approved, they typically target both ITD and TKD mutations. So intensive chemotherapy candidates, as have been mentioned, we would approach with 7 + 3 + midostaurin based off of the RATIFY study which I will talk about in a few minutes. And then for those ineligible for intensive induction, I think for the majority, there are multiple options that you could choose from from those nontargeted that are FDA approved in the upfront setting, but I think most people, based off of data that’s available, would go with venetoclax and HMA. And then for some patients who maybe are not even candidates for HMA-based therapy, you could potentially think about gilteritinib as a single agent upfront, but that’s off label use. But I have done that sometimes in my practice. And then for the relapsed refractory AML patients, what I do want to mention is you definitely want to recheck your mutational profile again because there can be clonal evolution, FLT3 mutations that were present initially might not be there with relapse, or there could be new FLT3 mutations present. And so you really want to be sure at that point in time of what — you’re making the best treatment choice for your patient. And so for relapsed refractory AML patients with FLT3-ITD or TKD mutations, based off of the ADMIRAL study, I think most people off study would pick gilteritinib as a single agent in most cases.

So for the mechanism of action for FLT3 inhibitors with midostaurin, gilteritinib, quizartinib listed here, essentially they bind into the ATP pocket or the kinase domain of the protein and cause the protein not to be phosphorylated and just essentially turns off that downstream signaling that causes lack of differentiation, proliferation and lack of apoptosis. And so the RATIFY study was the study led by Dr Stone that led to the FDA approval of midostaurin in the upfront setting with intensive induction and consolidation therapy. So it was a double-blind, placebo-controlled, Phase III study and the primary endpoint was overall survival. The study also looked at using the drug in maintenance, but the landscape of the FLT3 mutated disease was changing and many of the FLT3-ITD patients ended up going on to transplant and there were not as many patients who remained on maintenance therapy to really be able to tell if that should be used in that setting. And so the label is really just for in combination with induction and consolidation.

And so looking at the Kaplan-Meier curve for the primary intention to treat analysis at overall survival, you can see that midostaurin had an improvement at 74.7 months versus 25.6 months. And so based off of this, and even when censoring patients who went on to transplant, they still saw benefit. And so this is why patients would use midostaurin in this setting.

We’ve also wanted to look at using FLT3 inhibitors in the upfront setting for patients who are not eligible for intensive induction therapy. And so the LACEWING study, which has been mentioned, was designed to try to answer that question of using either gilteritinib alone, gilteritinib with azacitidine or azacitidine alone. And the gilteritinib only arm was closed early, but when they looked at an interim analysis of looking at the combination with azacitidine versus azacitidine alone, it didn’t appear that the primary endpoint of overall survival was going to be met and so the study was recommended to terminate for futility. And so I think there’s some abstracts that talk more about the data. They’re looking at it at a deeper level and so we’ll see what other findings come about from the study. And I think also from that, people were using some gilteritinib off label with azacitidine and I think people have moved away from that based off of this.

So now for the relapsed refractory setting. As mentioned, the ADMIRAL study really is what led to the FDA approval for using gilteritinib. And so patients were randomized in a 2 to 1 fashion to gilteritinib versus salvage chemotherapy that was preselected before by their physicians of either intensive or non-intensive therapy. And so the complete remission rates were higher with the patients CR, complete remission, with partial hematologic recovery was higher also in the gilteritinib arm. And then the overall response rate was higher in the gilteritinib arm. And so looking at the primary endpoint of overall survival, again, gilteritinib showed improved overall survival compared to salvage chemotherapy which included, again, intensive and non-intensive regimens. And so when you also censored patients who went on to transplant, we still saw that improvement with gilteritinib as well. And so that leads still to the use of gilteritinib in that relapsed refractory setting.

And so there’s a lot of interest with second generation FLT3 inhibitors, gilteritinib, quizartinib, crenolanib if you can continue to improve upon where we currently are. So there are studies looking at combination therapies, looking at these second generations in combination with induction, consolidation, post-transplant maintenance to help reduce risk of relapse for FLT3 patients who are able to make it to transplant. In particular for quizartinib, which I’ll talk about more in a little bit, the QuANTUM-R study was a Phase III study versus salvage chemotherapy that did meet its primary endpoint, but when it went forward with the FDA was not approved in that setting. And so it’s being looked at in other settings as far as with intensive induction therapy. So it’s a second generation FLT3 inhibitor. It has more potent in vivo activity than other FLT3 inhibitors to date. But FLT3-TKD mutations are an established mechanism of resistance to these patients and so you would not want to use this for TKD mutated patients.

And so the QuANTUM-First Phase III study is a study that’s looking, similar to RATIFY, of using quizartinib with chemotherapy, intensive induction and consolidation continued as maintenance compared to a placebo-controlled arm with the primary endpoint of event free survival, overall survival. And it was just announced that the study did seem to meet its primary endpoint of overall survival and so we’ll see as things move forward with this for these patient populations, what’s going to be the next step for FLT3 inhibitors for frontline therapy and where the field will move. And so there are some abstracts here at ASH with quizartinib looking at resistance mutations with RAS/MAPK and then also looking at it in combination with azacitidine and in other settings of MDS or MDS/MPN overlap with FLT3 or CBL mutations.

So now I’m going to move on really quickly to IDH mutations. So I think that we’ve had a lot of conversation. There’s still a lot of controversy about frontline therapy for these patients, but the majority of people would use venetoclax/HMA and then IDH inhibitors for those people who are not candidates for that. And so in the relapsed refractory setting, again, they’re specifically FDA approved for ivosidenib for IDH1 mutated and enasidenib for IDH2 mutated disease. And so I think this is a figure that’s been shown quite a bit, but just the mechanism of mutated IDH makes 2-hydroxyglutarate which is an oncometabolite and using these targeted therapies, is able to turn that pathway off.

And so ivosidenib in relapsed refractory IDH1 mutated AML, this study led to the FDA approval with the 500 mg daily in 125 patients showing an overall response rate of 41.6% and a CR rate of 21.6%. And in that study, there was a small cohort, 34 patients, who had newly diagnosed IDH1 mutated AML. And based off of the findings of an overall response rate of 54.5% and a CR rate of 30.3%, this was also FDA approved in the frontline setting for IDH1 mutated AML. The AGILE study is an ongoing study that is looking at adding ivosidenib to azacitidine and it appears that it’s going to have favorable results for its primary endpoint of event free survival. And so this will be presented also at ASH. And then enasidenib has similar response rates in the relapsed refractory setting. It also has data to support. This is a study from BDML showing response rates of 48% with monotherapy. And so there is within the NCCN guidelines that this may be an appropriate therapy for some patients with newly diagnosed IDH mutations.

And there’s lots of ongoing areas of investigation, again, in combination therapy, post-transplant maintenance. Also, with intensive induction therapy, the Phase I study has been completed for that and now it’s a randomized study looking at by the HOVON group.

And then lastly, about the VIALE-A study. I think this was gone over quite a bit. But looking at CR, CRi rates, the rates are higher in IDH1 and 2 and FLT3 mutated disease compared to the placebo-controlled arm. The overall survival was only really met with the IDH group and not with the FLT3 group. And so those lead to the questions of duration of response. And so we need to look at those patients a little bit differently. But that’s currently the best option of treatment we have. And so also as mentioned, there’s lots of areas of ongoing investigations with targeted therapy combinations as listed here. And so I think the field is really going to change remarkably over these next few years of how we approach patients.

DR ERBA: Oops. There you go. So, Alice, one of the questions from the audience is, do we see molecular responses with the IDH inhibitors like we do with FLT3 inhibitors?

DR MIMS: So you can with some patients with the IDH inhibitors. And so the question though is, as we’re learning more about MRD in patients, what’s meaningful, what’s the timepoint, where do you — what do you do with that? But, yes, you can see some of the molecular responses with these treatments.

DR ERBA: And would you prefer — so you have an IDH mutated patient, cost aside, would you use an IDH inhibitor or would you use HMA/ven?

DR MIMS: That’s always a discussion to have with the patient. I’ll be honest with you. I don’t blanketly just go to HMA/ven. I talk about their different options. They’ve not been compared heat-to-head. I do think they’re some potentially better quality of life components with an IDH inhibitor, but I think that really needs to be studied to have a better answer for that. And so it’s really kind of goals of the patient. The majority, ven/HMA, but there are some I would do a single agent IDH inhibitor.

DR ERBA: Yeah. I’ve used the IDH inhibitors less commonly than aza/ven there, but when I do, it’s in a patient who has maybe marginal performance status and already has an active infection. And one thing that has been reported is the counts seem to come up very quickly, even within cycle 1. And I’ve seen that in my limited experience. I don’t know if others want to comment on that. Okay. Thank you. I think we’re ready for Geoff to take the stage and we’ll move on. And we’ll play the video.

Management of Secondary AML; New Directions in AML Care

DR LOVE: The next case is a patient of Dr Anna Halpern. A 69-year-old man who had previously been managed with ESAs and luspatercept for MDS and was then found to have AML.

DR HALPERN: We treat him with CPX-351, as he fits the profile well for that, and he actually obtained a good remission that was negative for MRD. And he was able to move to a reduced intensity conditioning allogeneic transplant.

DR LOVE: I’m curious whether you’ve ever used CPX as an outpatient?

DR HALPERN: We’re a pretty unique institution in that we actually do outpatient post-induction care for patients getting intensive induction chemotherapy. We treat many patients with high-risk MDS and AML with intensive regimens in the outpatient setting. So for us, CPX is no different. And we can give it outpatient or inpatient.

DR SHARMA: How do you follow-up these patients if it’s done as outpatient? Patients that we have used CPX, what I have seen is that it seems to be better tolerated. But it seems like it tends to cause more prolonged thrombocytopenia. That’s the impression that I have gotten. Is that true? Is that your experience as well using this agent? Is CPX better tolerated for patients? And are there subsets of patients who would be not a candidate for intensive 7+3, for instance, chemotherapy, are they going to be eligible for CPX? Are we going to be able to take more patients to transplant as in better outcomes by using CPX?

DR ERBA: Sasha, do you want to address those?

DR PERL: Yeah. Sure. So the first question was, what’s the use of CPX in the outpatient setting? One advantage of the drug and its administration is it’s infused over 90 minutes rather than continuously over 7 days and that facilitates the ability to give it in the outpatient setting. I personally have not induced patients with CPX in the outpatient setting and then admitted them right after they’ve gotten the drug, but I know that there are centers doing that. So that is reasonably standard if you’re set up for that. But I’ve certainly consolidated patients with this in the outpatient setting and it is rather easy to do it that way. If your center is set up for that, that’s great. So I think it really depends on what support you have for that.

In terms of the question that came up for patients who may not be eligible for intensive chemotherapy, are they better served by getting CPX? Is it really kinder, gentler chemotherapy? I think the available data say no. That this really should be reserved for patients who are fit for intensive approaches. And the primary benefit when you look at the randomized comparison of CPX to 7+3, was not just in terms of the remission rates, but really was in terms of the outcome when patients went to transplant. So I think of using CPX in somebody that I’m going to use these results with induction to bridge to a transplant, ideally immediately thereafter and not use a chemotherapy consolidation or not a prolonged chemotherapy consolidation. If you looked at the outcome on that study with patients who didn’t get transplant —

DR UY: Sasha, you’re stealing my talk.

DR PERL: Oh my gosh. I’ll leave it for you, Geoff. If you look at those patients, Geoff will answer the question then.

DR UY: Yeah.

DR PERL: But that’s my goal in those patients is I do use CPX, I do use it as part of curative therapy. I think you should be using that for intensive treatment rather than trying to tone down the intensity because it actually does cause longer myelosuppression. Yeah, you keep your hair. That’s nice, but as I say to every patient, I can’t tell you whether you’re going to have a lot of side effects or not a lot of side effects, but I can guarantee your hair will grow back before mine.

DR ERBA: Okay. And so let’s move on to the polling questions. So reimbursement and regulatory issues aside, which initial treatment would you recommend for an older patient who is not eligible for intensive chemo who develops AML with no actionable mutations while receiving aza for higher-risk myelodysplastic syndrome? And most people would add on venetoclax. And I’m going to guess that the others were clinical trial. Rich, what do you think?

DR STONE: This is a very perplexing situation where patients had azacitidine for high-risk MDS, now has AML. And we see this and we’re dismayed by it because there isn’t a lot of good data. There’s no data with HMA/venetoclax really because the VIALE-A trial excluded those patients. There is data with low-dose cytarabine and venetoclax because of the VIALE-C trial published by Dr Wei did include those patients. And that was in fact probably one of the reasons why the outcome was a little bit less robust in the VIALE-C trial compared to the VIALE-A trial. So at least you’ve got some justification for doing that. Low-dose cytarabine and glasdegib was based on a randomized trial of low-dose cytarabine versus low-dose cytarabine and glasdegib in untreated patients, so that wouldn’t really work. So I think this is a case for a clinical trial. CPX-351 sounds like a good idea, but you’ve told the patient is ineligible for intensive chemotherapy. And Sasha just made the persuasive point that that patient shouldn’t get CPX-351. So this is a clinical trial of those data with low-dose cytarabine and venetoclax.

DR ERBA: This really doesn’t tell us though if the patient was responding to the HMA. Were they primary refractory or did they respond for a long time and then progress? And I don’t know. There aren’t great options if they don’t have an actionable mutation. The easiest thing I find to do is just give them another cycle with venetoclax. And I’ve actually done that and seen responses in people who have not responded to the first 2 cycles. Now that might not be enough. I know what you’re thinking. But, you know, 2 cycles and you’re still getting —

DR STONE: That does work if the patient still has MDS. There’s data that’s supporting adding venetoclax to azacitidine.

DR ERBA: Yeah.

DR STONE: Not so much if they have AML now, but maybe true.

DR ERBA: Okay. Next question. Which initial treatment would you recommend for a younger woman who is eligible for intensive chemotherapy with a history of breast cancer for which she received adjuvant anthracycline chemotherapy who now presents with AML with no actionable mutations? And there are your choices. And most people chose on label use of CPX-351. Sasha?

DR PERL: I think that’s very reasonable. Do recognize that this isn’t an anthracycline containing regimen. It’s not anthracycline-free. It’s purple not red, but it’s got an anthracycline in it. So just be aware that there is a risk for toxicity. It was equivalent in each of the arms. So if you’re comfortable using an anthracycline-based regimen to treat the therapy-related leukemia, there’s no free lunch here. And the other question is, just what’s the equivalent daunorubicin dose here? I think that’s still a little bit to be figured out, but probably comparable to what was seen in the 60 mg/m² arm of the 7+3 comparison. I think it was equivalent across both arms in terms of cardiotoxicity on that study.

DR UY: So an interesting point. If you have received 4 cycles of AC, you have been ineligible for the randomized Phase III as I’m sure your dose of anthracycline was too high to receive the course.

DR ERBA: That’s exactly right. Yeah. And for me, it also depends on, you know, this is where molecular analysis might be important. So if this is a patient who got AC and 1 or 2 years later has AML with a core binding factor translocation which happens rarely, more commonly a KMT28 rearrangement, I may still give that person intensive chemotherapy, but if it’s P53 mutated, then I’m going to be thinking HMA/venetoclax.

DR PERL: I just had a therapy-related AML in a breast cancer patient who is an 821 this past week and I gave her 7 + 3 with GO.

DR ERBA: Yeah. I agree. They’re not common, but you have to look for them. Next slide. Is there another? Okay. Do you generally admit to the hospital all patients who are receiving CPX-351? Alice?

DR MIMS: So currently in our practice, we do, but I think we’re moving towards where we’ll do that more of an outpatient setting. We have the ability to give like HiDAC consolidation, but it’s just more of things like clinic space and that type of thing. So yeah.

DR ERBA: Okay. Did you want to make a comment?

DR STONE: Yeah. Just briefly. I think one of the key reasons for giving the CPX-351 in the clinic is cost reasons. Unfortunately, that’s the way it goes and it’s also better for patients. I admit them on day 10 after they get the 3 doses of CPX in the clinic.

DR ERBA: Yeah. I agree. That’s what we do as well.

DR UY: Okay. So I have the pleasure of talking about secondary AML and new directions in AML care. And so we know that most cases of AML arise de novo, but AML also can occur after an antecedent MDS or myeloproliferative neoplasm and also can occur as a complication of cytotoxic chemotherapy and/or radiation therapy that’s administered for an unrelated disease. And so with the therapy-related AML there’s 2 major types that have been identified. AML that occurs after an alkylator or ionizing radiation. These cases are typically associated with losses of chromosome 5/7, complex karyotype TP53 mutations. And then there’s another subtype that’s associated with administration of DNA topoisomerase II inhibitors. These tend to have a shorter latency period and they characteristically sometimes have rearrangements of the chromosome 11, the long arm of q23, which is where the MLL or KMT2A gene is located. And so when you look at secondary AML as a population compared to de novo AML, there’s a higher frequency of adverse-risk karyotypes in genetics and these patients are more likely to be older, have poor performance status and higher — more comorbid conditions.

And so we’ve learned a lot through next generation sequencing techniques doing these serially about both the clonal heterogeneity of these diseases as well as the clonal dynamics. And so if you look at these cases serially, you can see a number of different patterns that can emerge in terms of their mutation burden. In some cases, secondary AML arises as a form of linear evolution where you sequentially acquire new mutations in the dominant clone. You can also see examples of branched evolution where the secondary AML can arise from either the dominant clone or even the subclone that’s present at the time of diagnosis. And we also know that the natural history of MDS and secondary AML is often influenced by the type of treatment that you give. So in some cases, we can administer a drug like a hypomethylating agent that can achieve a remission and when they relapse and evolve to secondary AML, they acquire new mutations in the dominant clone. Sometimes, you administer a treatment and you can see disappearance of a subclone, but the dominant clone remains and the patient still has residual disease. And knowing these clonal dynamics is important as we think about how to choose therapy. It also emphasizes the need to reevaluate these patients genetically at the time of relapse.

And so, again, we know that mutations in MDS and AML are often shared, but the type and frequency of these mutations from when a patient has MDS to secondary AML tends to change over time. So mutations such as TP53, mutations in epigenetic modifiers such as TET2 and DNMT3A tend to be present at both the time of MDS and at the time of evolution to secondary AML suggesting that these are early events whereas mutations in activating genes such as — activating receptors such as FLT3, NRAS, KRAS, PTPN11 tend to be late events and are often subclonal in nature.

And so this is just a population-based study from DelMar showing that the outcome of patients receiving intensive chemotherapy with secondary AML and therapy-related AML are much worse than de novo disease. And so right now, there’s currently only 1 FDA approved therapy specifically geared towards secondary AML, that’s the CPX-351 which is a liposomal formulation of daunorubicin and cytarabine. It seems to maintain drug exposure for at least a week and maybe selectively taken up by leukemic cells in the marrow. And so this is based on the randomized Phase III study. Over 300 patients treated and they were randomized to either CPX versus 7+3, both in induction and consolidation. So these included primarily older — these were only older adults and they had either therapy-related secondary AML or AML with an MDS-related karyotype.

And so now based on this data, we know that CPX results in higher rates of both complete remission and CR + CRi. And with 5-year survival data now mature that the survival benefit for the CPX group is maintained. And as Sasha alluded to, one of the most interesting aspects of this trial is that if you look at the number of patients who were transplanted. So in this subgroup of patients, typically we think of transplant as the preferred treatment option for consolidation as very few of these patients are cured with chemotherapy alone. If you were given CPX in induction, more patients went to transplant, more older patients went to transplant, more patients went to transplant and remission. And you can see that the long-term follow-up looks relatively impressive. If you could get to transplant, 56% at 3 years.

And so if you look at the toxicity with CPX versus 7+3, they’re a couple things that stand out. First, that both neutrophil and platelet recovery happens about a week later than conventional 7+3 and if you look at the rates of bacteremia in these patients, it appears to be slightly higher in the CPX arm. But counterintuitively, actually the early mortality is less with CPX at both 30 and 60 days when compared to 7+3. And we think that this may be a reason why you saw an overall survival benefit and also improved transplant outcomes because it seems to be slightly better tolerated.

Even though we know that this compound provides a survival benefit in secondary AML, we do know that there are specific subtypes that still do quite poorly. So as I mentioned, P53 tends to be one of the worst actors in AML and was present in about one-third of cases of secondary AML. And so if you — in the CPX trial, if you looked at the patients who had mutated TP53 status, those patients really did extremely poorly and it didn’t really matter if they got either CPX versus 7+3. The outcomes were uniformly poor. So that’s where I got back to my message earlier that I generally am unenthusiastic about giving intensive chemotherapy to older adults with P53 mutations.

And so what about low intensity therapy? So the standard of care, as we’ve mentioned, is hypomethylating agents plus venetoclax. So this was data presented by — or published by MD Anderson looking at their outcome of 10-day decitabine plus venetoclax. As you can see, that even though we think of this treatment as being better tolerated, leading to higher response rates, the P53 mutation population still did dismally with the median overall survival of less than 6 months, only about 5 months.

Again, when we looked at the landmark VIALE-A study. So the left-hand side shows the overall study outcome for all patients and the right-hand side looks at the subgroup analysis. My little box is 1 mutation too low. But if you look at the P53 outcomes, there wasn’t clear benefit for receiving azacitidine plus venetoclax over azacitidine alone in that specific subpopulation.

So it’s clear that we need better therapies for this disease. So what’s out there? So one agent that people are very excited about is — are agents targeting the CD47. And so what CD47 is is it’s been described as the don’t eat me signal. It’s typically present on cancer cells that can be upregulated. It’s known to be upregulated on leukemia stem cells. And what it does is it binds the receptor presence on macrophages called SIRP alpha. And what it does is it inhibits macrophages from phagocytosing these cancer cells. And so if you come in with an anti-CD47 agent or blocking agent, what you can do is you can prevent these — you can turn off this don’t eat me signal and allow the macrophage to phagocytose these cancer cells. And so there’s a number of these drugs in commercial development and magrolimab is probably the furthest along. And so David Sallman from Moffitt presented some of this data about 2 years ago in combination with azacitidine in AML and MDS. Again, it was a single arm doublet-type therapy. And so what they found, or what he found, is that the combination of magrolimab and azacitidine induces high response rates in AML. This is the waterfall plot. Overall response rates in the 60% range. And this high response rate was seen also in the P53 mutated population. What he also showed is that the overall survival appeared to be encouraging in both the P53 wild type and mutant patients. And so they saw an overall survival, a median overall survival, of 12.9 months in the P53 mutant population. The caveat is this is very, very preliminary data and if you look at all the events, they tend to be in the 6-month range or less. So we really need mature results from this study to really evaluate whether or not this is going to be a promising therapy in P53 patients.

Another area of interest are menin inhibitors. So I mentioned that MLL rearrangements are often linked to therapy-related AML. And so there are these drugs that are being developed for both MLL rearranged and NPM1 mutated AML. So menin acts as a scaffolding protein for MLL or KMT2A. And so what these menin inhibitors do is they disrupt the interaction between menin and MLL and they don’t allow this complex to turn on and upregulate HOX genes which we think is important for the development of leukemia. And so there are 2 orally available menin inhibitors currently in Phase I studies, KO-539 and the SNDX compound 5613. And these are both being tested in MLL and NPM1 rearranged leukemias. For NPM1, it’s thought that the wild type MLL menin interaction is important. And so there is some preliminary Phase I data presented at ASH last year that’s showing as a single agent, the KO-539 does induce some clinical responses. Again, this is very early preliminary data. And at ASH this year, we’re also going to see some data for the second menin inhibitor, the SNDX-5613.

So these are some of the abstracts that are being presented looking at CPX combinations. I won’t go through them in the interest of time, but happy to answer any questions. Okay. That’s it.

DR ERBA: Wow. Okay. Well we have a few questions then for you.

DR UY: All right. Let’s hear them.

DR ERBA: Okay. So if a 65-year-old with AML starts on HMA with venetoclax as you are not sure of his tolerance of 7+3, gets a CR and then you find out his karyotype is favorable, I assume that means core binding factor or maybe he had a nucleophosmin mutation, so he doesn’t need a transplant, how long do you consider — continue HMA with aza — with venetoclax?

DR UY: I will say that there’s no data to guide the situation. I will say that we know that probably higher doses or intermediate — higher doses of cytarabine are probably the most active agent in this disease, so I would actually consider, if the patient can tolerate it, like a reasonably high dose, maybe 1.5 g/m² times 6 doses of Ara-C in this patient as consolidation rather than giving continued HMA/venetoclax.

DR ERBA: Wow. I completely agree with that.

DR UY: Well then great minds think alike, right?

DR ERBA: No, no. But I thought of it too. Not another great mind like yours. No. I completely agree. Are you going to just continue or can you give them time limited therapy? Now they’re in remission, their performance status is better. Obviously, we have absolutely no data. But I think that would be an interesting tact. Although I try to get this data about the — from the FISH analysis and, you know, targetable mutations early on before making that decision. But if you’re in that situation, not unreasonable.

DR PERL: The only thing I’d throw out there is this is a perfect patient to measure MRD in. And I think if you’re not clearing MRD even though it looks favorable, these patients do have a high relapse rate. And I have had some patients who relapsed after transplant and CR2 who had core binding factor rearrangement that I did treat with ven/aza only because they were too close to the transplant to get anything else and they have done beautifully with it. But these are anecdotes, these aren’t, you know, real data. But you can measure MRD in terms of the quantity of the fusion products by RT-PCR and this is a good setting for it.

DR ERBA: Well bringing that up, actually it brings up that question about the AML patient with nucleophosmin mutation and a FLT3-TKD. So favorable-risk, maybe not bringing them to transplant. Alice, are you using the nucleophosmin RT-qPCR to follow patients like the — Dr Ivey — Professor Ivey from the MRC, their data in the New England Journal showing you could distinguish patients who are at higher risk of relapse and deciding on transplant based on that?

DR MIMS: Yeah. We are using that for MRD testing.

DR ERBA: Okay. Well why don’t we stay on time. I think we’re good.

DR UY: Okay. Thank you.

DR ERBA: Okay. Okay. And then I’m going to ask Harry to come to the podium. Here I am. I’m not going to go to that one. I’ll stay here. And we’ll roll the video. Then, we’ll get into some discussion.

Current and Future Management Approaches for Myelodysplastic Syndromes

DR LOVE: The next case is from the practice of Dr Priya Rudolph. A 72-year-old woman who she previously treated with TCHP for HER2-positive breast cancer 5 years ago. Recently, the patient was noted to have pancytopenia which led to a bone marrow biopsy.

DR RUDOLPH: Her MDS was classified as excess blast Type 1 with an IPSS score of intermediate 2 risk and revised IPSS score, which put her at a very high risk. Would you consider giving azacitidine/venetoclax up-front rather than treating her with single-agent azacitidine? So why not treat her like an AML at this point? How about daunorubicin or cytarabine? How about CPX-351?

DR HALPERN: How are they using and dosing venetoclax and HMAs in MDS? Off label certainly, but high-risk MDS, close to the label? And lots of studies coming out now. ASH will be full of it. So, yeah, there are sort of nuances of venetoclax dosing in MDS and management of cytopenias and prolonged cytopenias. For the first cycle of azacitidine/venetoclax in a patient with MDS-EB2, would you give venetoclax for 28 days? 21 days? 14 days? Or not start at the first cycle?

DR SHARMA: In patients with myelodysplastic syndrome who are started with, for instance, azacitidine therapy and they have progressed and gone on to have AML patients who are not transplant candidates, have you used low-dose cytarabine in combination with alternative HMA agent? I have really not had very much experience with low-dose cytarabine in combination, but the VIALE-C study did study this, but I have not used it. I would be interested to know, is there any situation where you would use low-dose Ara-C in combination with venetoclax? The other question is, we get myelodysplastic syndrome patients who are treated with HMA therapy typically and the plan is to go on to have allogeneic stem cell transplant. So let’s say they started off with blasts percent of 5% despite being on azacitidine therapy, their blast count either doesn’t go down or it only goes up a little bit, is it important to cytoreduce these patients before going into allogeneic stem cell transplant? Is there any change in outcomes? Or does it make sense not to wait too long and take them to transplant right away with persistent disease?

DR ERBA: So those are some tough questions and that’s why we left those to our most senior member here, Rich Stone.

DR STONE: Well thanks for pointing out that I’m the oldest one here. Moving ahead though. Those are good and practically important questions. For Dr Rudolph’s patient who had TCH for breast cancer therapy and now has MDS-EB1, it’s important to know, as you pointed out, Harry, what the patient’s molecular and cytogenetic factors are because that may well influence how we treat her. Nonetheless, I would not use azacitidine/venetoclax off protocol in a patient with MDS at this point in time, even though I’ll come back to that with regard to Dr Halpern’s question. Would I use CPX in a patient with EB1? No, I would not because there’s really no data supporting that. There are low-dose CPX trials with venetoclax actually going on now but, again, they’re mainly for unfit AML patients. So for the patient that Dr Rudolph presented, I would use azacitidine alone, but it really depends a little bit on what the molecular and cytogenetic features are and, of course, if the patient’s fit enough for a transplant. Even at age 72, we might consider that either straight away or after some azacitidine. And I’ll come back to that with regard to Dr Sharma’s question.

The next question is how do we use HMA and venetoclax in MDS. And I think I already alluded to this a little bit in my response to the prior question, but we should be very careful to point out that there’s a Phase III trial going on right now comparing aza to aza plus ven, analogous to what was done in the VIALE trial, but for MDS, for high-risk MDS. And that’s ongoing. We don’t have the data. My colleague, Dr Garcia, presented last year at ASH, and will be presenting this year at ASH, uncontrolled data with the combination of azacitidine/venetoclax in MDS. And the data, frankly, is very exciting. And it’s been widely adopted even before the results of the Phase III trial were out. But I think we’ve been tripped up by that in the past. So I still relegate aza/ven to experimental therapy in MDS. I’ve also heard people say, well why don’t we — I need a response because the patient is going to transplant, I need a rapid response, aza/ven let’s do it. But we don’t know if it’s going to beat the patient up unnecessarily. I will say if you are going to use aza/ven for MDS, you should use it according to the way it’s being used in the Phase III trial that I mentioned which is to say standard azacitidine dosing with 14 days of venetoclax, not 21, not 28, 14. Even that might be too much, but that’s the way it’s done in the Phase III trial based on the Phase I trial that has been presented, uncontrolled fashion on trial.

So the next question I’d like to address is Dr Sharma’s about the role of cytoreduction prior to transplant in people who have MDS. This is a great bugaboo in my mind. It — there’s a lot of heat and not much light about this. Typically speaking, I will, for example, at my institution where Drs Koreth and Cutler work who both published saying you should transplant patients who have higher risk MDS immediately and delay transplant for lower risk MDS until progression, I’ll call them and I’ll say I have a patient with 10% blasts, please take them to transplant now according to your paper and they’ll say no, Rich, please give them some cytoreductive chemotherapy first because it’s going to take me a couple of months to get the unrelated donor, that most of these older patients need, going. And during that time, you might do me a favor by getting the patient into a lower burden of disease before their transplant. I think that the results are clear that if you go on to transplant with a lower disease burden than a higher disease burden, you do better, but that doesn’t mean it’s the chemotherapy that got them there. There may just be a biological phenomenon that by giving the chemotherapy before the transplant, you’ve identified patients who are going to do well, almost like a chemotherapy stress test. So we should be honest about what we’re doing. I think practically speaking, giving a couple cycles of azacitidine before a patient with MDS is going to have a transplant gets to the transplant I think is entirely reasonable. And I think I’ll stop there.

DR ERBA: But, Rich, if the transplanters refuse to take the patient because it’s still 5.3% blasts, would you give that patient venetoclax in addition to azacitidine?

DR STONE: If they failed azacitidine, yes. If they’ve not failed azacitidine yet, no.

DR ERBA: Okay. Yeah. This is after a few cycles. I think that was the question. I agree with that.

DR STONE: After. Yeah. If they haven’t, you know, of course, I would do that for them.

DR ERBA: We don’t know the answer, but our transplant colleagues know the answer. They want fewer blasts in there.

DR STONE: Well they want to take the best — I don’t blame them.

DR ERBA: Right.

DR STONE: If you can’t get somebody’s blast count to budge with azacitidine, maybe even azacitidine/venetoclax, the transplant’s going to not go well.

DR ERBA: Agreed. Especially a nonmyeloablative in a 72-year-old. Okay. Let’s go to the polling questions. In your opinion, which of the following approaches provides the best chance of therapeutic benefit for a 78-year-old otherwise healthy patient with newly diagnosed high-risk MDS with a TP53 mutation? Clinical trial participation. Geoff, do you agree?

DR UY: Like I’ve always said that these patients need something and we don’t have an answer yet. So I’m always in favor of clinical trials when available.

DR ERBA: Okay. Next question. Have you administered or would you administer venetoclax/aza to a patient with high-risk MDS outside of a clinical trial? And I haven’t, but would for the right patient. I have, one-third. And I haven’t and would not. Okay. So here, panel, have you or haven’t you? Raise your hands if you’ve done it.

DR PERL: Frontline or at some point?

DR ERBA: Yeah. For high-risk MDS, trying to get them to transplant or — have you used it?

DR PERL: Yeah.

DR ERBA: I agree with you, Rich. We don’t have the data, but trying to get them to transplant, you get quick responses. That’s the thing. And that might be important as well. But I — you know, it’s an unsettled question.

DR PERL: But if it’s an area you described, the transplanter says whatever the blast percentage, I want it lower. That’s variably the case.

DR ERBA: Right. So we didn’t get to pick our topics, by the way. They were assigned to us. And so you might ask, well how did these topics get assigned? Well my colleagues here have been actually intimately involved in the development of the drugs that we now use in clinical practice. And so that’s how those topics got assigned. So how’d I get MDS? Well I think Neil Love said, what are we going to do to keep Harry from talking all night? Well let’s give him a topic that nothing is happening in. And he made the mistake of giving me MDS. But they also made the smart move of putting me at the end. So if I do go long, 9:00, the door is right there. So why don’t we get started though.

Okay. So what do we know about MDS? We know that the prognosis of patients with MDS is quite variable. Many of us have made our academic careers looking at prognostic features. Prognostic models have been developed starting with clinical prognostic markers, models. The one that we use is the Revised International Prognostic Score based on karyotype, blast percentage in the marrow and actually something very important, the degree of cytopenias. And so we can assign a risk to these patients and, of course, you can then look at their prognosis in terms of overall survival and leukemia free survival.

But we now know that pathogenic mutations are also very important in determining the prognosis of patients with MDS. And we know that the number of mutations that we find correlates with the grade of the myelodysplastic syndrome. So lower grade MDS tending to have fewer mutations and higher grade MDS tending to have more mutations. And having more mutations isn’t good as shown here by these 2 different datasets looking at the effect of increasing number of pathogenic mutations associated with either inferior leukemia free survival on the left from Elli Papaemmanuil and on the right, you see Rafael Bejar’s data for overall survival.

We do know that you can incorporate or that this mutational data can actually help then further refine the risk stratification of patients with MDS. Rafael Bejar’s group showed that with a set of 5 genes, that you can actually distinguish higher and lower risk among the lower risk, clinically lower risk, MDS patients. Not much of a benefit or an effect in high-risk MDS. And models have been developed that can be based on IPSS-R plus a gene set. This is data published by Haferlach a few years ago showing that this can be incorporated into decision making. What we don’t know is if it’s prognostically important. But if you have a clinically lower risk patient with a higher risk mutation, do you take that patient to transplant before they progress? We don’t know the answer to that.

So how do we approach this disease? In patients with lower risk disease, however you’ve chosen to define it, we will observe the patient if their cytopenias are trivial and they are not having symptoms from it. If they have isolated cytopenias, we tend to start with hematopoietic growth factors, the ESAs for anemia, thrombopoietin agonists can be used for thrombocytopenia with the caveat that if patients have increased blasts and still lower risk disease, they may have a higher risk of progression to AML. So be careful there. If a patient has multiple cytopenias and a number of features that seem to maybe predict for a response to immunosuppressive therapy like a more hypoplastic disease or PNH-like clone, you might consider using immunosuppressive therapy or a hypomethylating agent.

Now getting back to anemia, if a patient fails to respond to an ESA, you can consider a trial of an IMiD like lenalidomide, especially if they have a deletion 5q. Now I got this from the ASH Educational Book, so it’s got to be gospel, right? It’s from here. And Mikkael Sekeres said he would start with an erythropoietic stimulating agent first, even before lenalidomide according to this in deletion 5q. That’s what this says. I actually agree with that although there’s been data that was presented at last year’s ASH suggesting that patients have a delay in becoming transfusion dependent if you start with lenalidomide as opposed to placebo. Of course, there was no difference, however, in overall survival between those 2. And, of course, there was no discussion of the toxicity that comes along with starting the IMiD early.

But what I’m going to move to is a new hypomethylating agent that we can use here in myelodysplastic syndrome and luspatercept if the patient has MDS with ring sideroblasts. So let’s start with luspatercept. This is a trap protein. It binds ligands of TGF beta and appears to be very important in helping improve erythropoiesis. For some reason, patients with ring sideroblasts seem to have the most robust response and so the Phase III MEDALIST trial was done in patients with MDS with lower risk MDS with ring sideroblasts. They did not have to have an SF3B1 mutation. Pretty smart. That means there was no companion assay that had to be approved for luspatercept. It was based on ring sideroblasts. And these patients were receiving at least 2 units of blood a month and either had failed an ESA or were unlikely to benefit.

And the primary endpoint of the study was reached by 24 weeks. In that first 24 weeks, more patients became transfusion independent for a length of time of 8 weeks or longer with luspatercept, 38% versus 13%. And the other bar grafts are just looking at various times and various durations of transfusion independence and in each case, luspatercept was higher. Remember that you start at 1 mg/kg. It is a 3-week — every 3 weeks, it’s a subQ injection, but don’t forget you can dose-escalate and don’t forget the dose-escalation is different for MDS than it is for thalassemia and you can go up to 1.33 mg/kg here.

There was also an erythroid response, a secondary endpoint. And now in terms of toxicity, I think the one thing that stands out in terms of toxicity here is that there does seem to be more fatigue and dyspnea which is interesting early on with treatment with luspatercept that is poorly explained. But otherwise, fairly well tolerated.

We’ve been talking about oral cedazuridine and decitabine. You know cedazuridine is a drug that blocks cytidine deaminase and allows decitabine to be absorbed. The way it was approved by the FDA, quite amazing in this era of COVID. Probably one of the approvals that clearly came from the COVID pandemic. And in this study what they did was they showed bioequivalence between oral dosing of cedazuridine and decitabine and IV decitabine. The patients with lower risk — I’m sorry, intermediate and higher risk MDS, not low-risk MDS, were randomly assigned to start with oral cedazuridine/decitabine or IV and then the second cycle switched and what this complicated table says is that the PK parameters were quite similar. The response rates were what you might expect.

It’s a Phase II study, so there’s no comparator there, but you can see about a 20% CR rate which is what I would typically quote for a hypomethylating agent in MDS. And it could take time to achieve these responses. What’s interesting about the drug though, an oral drug, and what distinguishes it in my mind from oral azacitidine is it really doesn’t seem to have extra GI toxicity different than the IV which is quite important. But in terms of the other cytopenias, very similar to what was seen with IV.

Let’s move on to higher risk disease. And I’m not going to show you slides on azacitidine and decitabine. But instead, let’s talk about things that are new. I’m going to start with the data for magrolimab with azacitidine. You already heard what magrolimab is, a first in class anti-CD47 antibody. And you can see in this presentation from a couple years ago, the CR rate was 50%, overall response rate 92% in first line MDS patients. The toxicity that we need to be aware of — I meant to go backwards, sorry. The toxicity that we need to be aware of is that there’s an on-target effect on red blood cells and you can get early drop in the hemoglobin because of that. There is a mitigation strategy where there’s a ramp up of the magrolimab in the first couple of weeks from a lower to a higher dose.

We’ve been talking a lot about azacitidine and venetoclax. And Rich pointed this out, it’s very important. This study started out with a 28-day course of venetoclax and it was too toxic. It was just too myelosuppressive. And so what you’re seeing here is the Phase Ib/II study where they only used 14 days of venetoclax with azacitidine. The response rate is dramatic. It’s an 80% response rate overall, but look at the division there. It’s almost half and half CRs which to me means counts have recovered and marrow CRs. And I think that’s the concern that Rich was bringing up is the suppression, the myelosuppression that you get with this regimen.

However, a total of 16 patients, 21%, were able to go on to stem cell transplant and that might be where a regimen like this has a benefit. And here you can see the median time on study was 16 months and the estimated survival of 12 months was about three-quarters of patients. But as I said, the toxicity was myelosuppression and we really don’t know how to manage that. After you get them in remission, should you continue with just azacitidine alone or a shorter course of venetoclax? And I think we’re all going to be learning that as we go along. There was a larger multi-center Phase II study that confirmed these results of high response rates in both HMA naïve and HMA exposed patients.

Two last things to finish with, eprenetapopt plus azacitidine for TP53 mutated myeloid neoplasms. Remember eprenetapopt (APR-246) is a drug, IV drug, that gets metabolized and the metabolite is able to refold the mutant P53 protein, which are typically missense mutations, into something that is active. The major toxicity that was seen was a central nervous system toxicity of ataxia dizziness due to a lipophilic metabolite that’s also produced. But what was shown here and published by our colleague at Moffitt, David Sallman, was a very high overall response rate in 40 patients with MDS of 73%. And you can see the CR rate of 50%, quite impressive. And you can see the swimmer’s plot and the median overall survival of 10.8 months which seems better than you might expect for many of the survival curves we’ve seen in this subset of patients. But really what we need to know is, does it improve survival? And what we learned, however, is from a Phase III study that was done. We have the top line result that’s been reported in the intent to treat analysis of 154 patients with P53 mutated MDS. The eprenetapopt with azacitidine CR rate was higher, 33% versus aza alone 22%. But unfortunately, the P value was not statistically significant. Hopefully, we’re going to see more development coming with this drug. And there are clinical trials going on.

Let’s not forget about use of ivosidenib or enasidenib in IDH mutated MDS. In the Phase I studies, we had a small cohort of patients with those mutations, about 12, saw very high response rates of like 11 out of 12 patients. Remember those were patients who had been previously exposed to hypomethylating agents. Here, you can see a Phase II study multi-center trial with both HMA naïve and HMA failure patients treated with enasidenib if they had IDH2 mutated higher risk MDS. And you can see in the HMA naïve patients, a very high overall response rate of 84%. The CR rate, however, still only about one-quarter of patients.

Let’s not forget about transplant. The BMT CTN pulled it off. They did the study 1102, really mandated by CMS, to show a benefit of reduced intensity allotransplants for our patients, older patients, with MDS. And so they did this study where patients were sent to allo transplant or continued on hypomethylating agents or best supportive care between the ages of 50 and 75. And you can see there was a statistically significant difference in 3-year estimate of overall survival and leukemia free survival. Now remember in these transplant studies, there’s going to be noncompliance. People who are supposed to get just HMA end up getting a transplant. People who are supposed to get a reduced intensity transplant don’t or they get a full myeloablative transplant. So even if they look at the data as treated by reduced intensity or hypomethylating agents, the difference is even more profound.

So I think there’s a challenge in treating these patients. When we see them, we have to clearly define what is going to be the goal of therapy and we tailor it to the patient, their comorbidities, but also to the disease risk and to what the patient expects out of life at that point, what are their goals in life. Therapies for lower risk MDS generally aim to improve blood counts and hopefully quality of life at the same time. Therapies for higher risk disease hopefully will do the same thing but, of course, also increase life expectancy. I think many of us are generally disappointed with what we have had for the treatment of this disease. Hematopoietic growth factors, hypomethylating agents, we still don’t know how they really work in MDS, frequently disappointing. And so MDS patients really should be encouraged to participate in clinical trials evaluating agents that target either the pathogenic drivers and I think we’re going to see some interesting things with the spliceosome drugs targeting the spliceosome which plays a big role in MDS and also the immune environment. And it’s exactly 9:00. And we’re done.

We do have — we don’t have time, but I will go to a couple questions. Feel free to leave. So what are the promises of the more advanced therapies in trials like venetoclax, magrolimab and sabatolimab? I just didn’t have time to talk about everything. The TIM-3 inhibitors are quite interesting and sabatolimab is the first drug, TIM-3 inhibitor, being evaluated. I still think we need a lot more data there. Sasha, would you like to say a few words about that question? You’re good?

DR PERL: I’ll echo what you said. We need more data.

DR ERBA: Okay. And why can’t you give an ESA with luspatercept? Probably insurance wouldn’t allow it. But it’s a good question. I don’t think we fully realize the value of luspatercept. It’s a single agent in patients who are ESA refractory, but should it be used — and with ring sideroblasts, but will it have activity? It does seem to have some activity outside of ring sideroblasts and that’s being explored. And in combinations, not just ESAs, but combinations with hypomethylating agents and other therapies need to be considered. So I would say the biggest issue of why you couldn’t consider doing it is we really have no safety data on the combination and typically, we’re using it in patients who are refractory to ESAs. I say the one thing I see quite often are patients who just continue on ESAs month after month after month and they’re still getting transfusions and everyone’s worried about stopping it because they say, well the transfusion frequency will go up. And I would say, prove it. And then we can decide if they should start again. Okay. I’m sure you all have parties to go to or something. It’s Friday night. So thank you very much for attending. I know we enjoyed it.