This has been an amazing discussion; I have learned so much from all of you, and I have enjoyed interacting with you this afternoon as we discuss what is new for our patients with acute myeloid leukemia [AML]. Thanks to all of you for this rich and informative discussion. Before we conclude, I would like to get final thoughts from each of you on exciting new developments or emerging agents that have caught your attention, and I will start with Corey.

I have learned a lot just by listening to your discussion. The fact that you are getting many more people into deeper and longer-lasting remission bodes well for the future of transplantation. The better the patients are that you send to us, the better we can perform, and hopefully, as we learn how to use your drugs better, the better our long-term outcomes will be for everybody. We are excited about the future of transplant in advanced myeloid malignancies.

Thank you, and thanks for being with us. Adam, a few words?

It is self-evident that genetics in AML is complicated. It is a complicated disease. The approaches to testing are many-fold. There are cytogenetic assays, there are FISH [fluorescence in situ hybridization] assays, there are single-gene assays, and there are NGS [next-generation sequencing] multi-gene assays. It would be wonderful if, in the future, there is a single platform to allow us to look at everything in 1 sitting. We are a ways away from that, but that may be on the horizon: Something like RNA sequencing would give us a lot of the information that we could get from other disparate forms of genetic assays. For the moment, we are stuck with the different technologies, which are great technologies. Each has advantages and disadvantages, so it is important for the user to be cognizant of the advantages and disadvantages of the respective assays, their turnaround times, what they are testing for, and what their sensitivities are in terms of tracking minimal residual disease [MRD]. As a hematopathologist, it is a wonderful area to be involved in, and we do our best to tell you what is going on with your patient so you can treat them appropriately. Stay in touch with your hematopathologist; they are your friend.

There is continual advancement in AML. It is exciting to see that the flurry of drugs that were approved in 2017 was not the end of the line, but it was actually the start of a lot of interesting studies that have happened since then, primarily in the area of combinations. It is exciting to see all these things come together and new avenues taking off.

I agree with Sasha. We are seeing a lot of novel combinations building on the new backbone of venetoclax-azacitidine or venetoclax as opposed to 7+3 chemotherapy-based regimens, which have been our backbone. I am excited about the immunotherapeutic approaches for both primary and refractory AML, as well as MRD-positive or low-burden disease. I am also excited by the potential that we may be able to, in a precision medicine way, target and have better therapies for patients with 

-mutant disease or MLL [mixed lineage leukemia] rearranged disease, for whom we had no therapeutic avenues available to us prior to this year.

What I find most exciting, having been in this field for 25 years—and not as a transplanter—is that there is a real focus on the majority of patients we see, the older patients at the end of their lives, who are facing a disease that can be catastrophic and obviously life-ending. What has troubled us all this time is that our approach has been always that this is a curable disease, yet when you think about it, even with what we have had until recently, the number of patients cured is quite low. Of course, that needs to be our focus, and what I have enjoyed about the last 3 years and the development that we see ongoing is that there will be patients who will not be eligible for curative therapies based on their biology or the disease biology, but we are evaluating new therapies that appear to be not only extending life but also improving quality of life. Those are important end points for our studies: improving quality of life, decreasing hospitalization, decreasing transfusions, and bringing meaningful responses to our patients. This has been an exciting time for all of us in caring for our patients with acute myeloid leukemia.

I want to thank you again, our viewing audience. We hope you found this 

® discussion to be useful and informative. Thank you.

Videos

Corey S. Cutler, MD, MPH, FRCPC; Adam Bagg, MD; Alexander E. Perl, MD, MS; Eunice S. Wang, MD; and Harry P. Erba, MD, PhD, share closing thoughts and emerging therapies on the horizon for the treatment of AML.

Future Treatment Landscape of AML

Before I finish this section, I want to come back to Corey. I am going to give you a wide-open topic. We talked about the first and only FDA-approved continued therapy for AML [acute myeloid leukemia] as oral azacitidine being just recently approved. How about after an allogeneic transplant? How do you think about which patients should receive a maintenance therapy there? I am going to have Sasha talk about 

 mutations in a second, but why don’t you talk about anything other than 

It is critical that we do something in the post-transplant setting because relapse remains the main cause of failure for patients with myeloid malignancies. It is far more important than graft-vs-host disease or infection these days. As you develop these novel, genomically inspired therapies to get people into remission, we are actively examining ways to use them in the post-transplant setting to minimize relapse. We are actively testing venetoclax in the post-transplant setting, and we are actively testing the APR-246 compound in the post-transplant setting for patients who are coming in with known 

, but certainly based on the SORMAIN trial data, most of us use some form of FLT3 inhibition in the post-transplant setting, and the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] is formally testing it in a randomized phase 3 trial looking at gilteritinib. All these targeted agents are fair game in the post-transplant setting. We need to learn how to use them properly in the sense of understanding drug-drug interactions and tolerability on a fresh marrow, so all that needs to be learned. Clearly, as you all develop novel agents to get people into remission, we are going to learn how to use these compounds in the post-transplant setting with a goal of maintaining remission.

Your points are well taken. The risk of relapse remains high, especially in some patients who go into transplant with MRD [minimal residual disease] or certain biological subsets of patients. It is not the end of the road; it should be seen as a therapy that we may be able to improve upon, as you mentioned.

Sasha, let me come back to you. Nowadays, we are treating patients who are ultimately going to be fit for a transplant. Most of them will have received intensive chemotherapy with midostaurin. In the near future, there may be a second-generation drug, but right now it is the first-generation type 1 inhibitor midostaurin. What do you recommend for patients with 

-mutated disease who have undergone allotransplant? As Corey mentioned, there are the SORMAIN trial data with sorafenib. There was also a smaller trial in the United States of midostaurin. I think it’s the RADIUS trial if I remember correctly. Do you try to get a second-generation drug like gilteritinib off-label for these patients because we do not know the BMT CTN study results? What do you do?

We do not have those data. To put everything out there in terms of what we know and expand on what Corey said, there are not 1 but 2 randomized studies that show either a disease-free survival or an overall survival benefit adding sorafenib post-transplant to patients who got an allogeneic transplant primarily in first remission, although the SORMAIN study included patients transplanted out of remission or in second remission.

One question from that study and from the Chinese study that followed it as well is this: In patients who primarily did not get frontline FLT3 inhibitor like midostaurin added to their induction chemotherapy, is the benefit still maintained there? The simple answer is that we do not know. One important takeaway from this is a) it is feasible, b) it looks like it works, and c) you would have to be nuts not to add it unless you thought there was going to be toxicity that you could not keep up with. Outside of a trial, I have been adding sorafenib for years when it was available and since then gilteritinib, but I did so without knowing whether it was better.

What we have learned in the intervening time is that there are real benefits to this approach, but we do not know that those benefits extend to everybody. Now that we are using a frontline FLT3 inhibitor, we do not know just how big that benefit is and if it is counterbalanced with toxicity issues that do not show up until years later. We are curing more and more patients who have 

 ITD mutation with transplant, so late effects are going to be important. That is not to say that these drugs do not have toxicities. They do, and we will see them borne out over years of exposure that we would never see in the relapsed/refractory setting treating patients with gilteritinib who would not necessarily go on to a transplant.

In patients who I treat with gilteritinib, who then go on to transplant, I give those patients maintenance as well. These long-term follow-up studies are going to be important, and 1 advantage of the BMT CTN trial is that it has a long follow-up. It is 2 years of therapy and then some to see the readout, plus it will get MRD data measured prior to transplant, and it enrolls a lot of patients from the United States, where the approval of midostaurin led to a large number of patients having received frontline TKI [tyrosine kinase inhibitor].

We will learn everything we need to know to see who benefits and if is this across the board, if it is for MRD-positive cases, if it is for people who did not have a prior TKI, etc. If there are these differences, then let’s tease them out and give this most rationally. If there are no differences, but there is a benefit to the TKI, then give it. If I am surprised, and there is no benefit, then I guess there is no benefit. We are going to learn all that from the study.

Patient selection for maintenance therapy post-allogeneic transplant in myeloid malignancies and thoughts on treatment of FLT3-mutated disease post-transplant with agents such as midostaurin.

Maintenance Therapy Post-Transplant in AML

Eunice, you mentioned CC-486 [oral azacitidine]. This is the latest of the FDA approvals for our patients with acute myeloid leukemia [AML]. On September 1, 2020, the FDA approved oral azacitidine for adult patients who have acute myeloid leukemia in first complete remission [CR] or CRi [complete remission with incomplete hematologic recovery] after intensive induction therapy who have not undergone or were not candidates for, as you mentioned, curative therapy. What they meant by that was curative cellular therapy or allogeneic stem cell transplant.

That approval was based on the study meeting its primary end point of an improvement in median survival from 15 months with placebo up to 25 months’ median survival with oral azacitidine. However, it should be pointed out that, if you look at those Kaplan-Meier curves, by 48 months, or 4 years, they are coming together around 20%. I agree with you that we should still be thinking about transplant for these patients, but for those who are ineligible for transplant for whatever reason, oral azacitidine presents an option for them. You need to know how to manage the GI [gastrointestinal] toxicity, and you need to know how to manage some of the myelosuppression. You can get these patients through this therapy, and they may benefit from an improvement in survival by delaying relapse.

At last year’s ASH [American Society for Hematology] Annual Meeting, our colleague from New York, Gail Roboz, presented data on the MRD [minimal residual disease] assessment. Around 45% of patients were MRD positive by flow cytometry prior to going on the study where they were then randomized between oral azacitidine and placebo. The benefit of oral azacitidine was seen in that group as well as the MRD-negative patients, as you mentioned, Eunice. On top of that, some of those MRD-positive patients became MRD negative over time. Whether they also got well enough to undergo transplant would be an important issue. It may be a great bridge to transplant, but we have no data looking at that. This is another therapeutic option for our patients who are not able to proceed to allogeneic transplant in first remission.

One of the challenges we have is getting patients with AML with 

 mutations to transplant. Sasha, do you want to talk to us about APR-246?

Sure. It is an interesting drug. It is perhaps unique among the therapeutic armamentarium in terms of being a drug that is being developed not just for 

 through its effects on unfolding that protein/ At least that is the purported mechanism of action. It is a drug that has been evaluated primarily in the context of hypomethylating agent [HMA] activity in 

-mutated MDS [myelodysplastic syndrome] and AML. In reality, because there is such a tight correlation between MDS and AML with that mutation—it is a spectrum of the same disease—the response rates are seen across the spectrum in terms of both MDS and AML responses with this new drug.

It was evaluated in combination with HMA in a study presented at EHA [European Hematology Association] Congress, but there was no update at ASH last year. A treatment-naïve or HMA-naïve population that was of median age in their mid-70s was treated on a study combining APR-246 with HMA, and the phase 3 of this approach has completed enrollment. The presented data showed a response rate in terms of CR and CRi that exceeded 50%. I believe it was 64% for the entire cohort, about two-thirds of whom had MDS but a third of whom had AML. Here, AML was defined by 30% blasts, not 20%, so it has a high response rate in this population, and it is certainly in the range that we would expect would be higher than HMA alone. This is promising going into the phase 3 setting, and we look forward to those data in the future.

There have been some toxicities with this drug, including neurotoxicity from it. It is an IV [intravenous] infusion. It takes a prolonged infusion, but the mechanics of it do not limit its administration in the outpatient setting. It is an interesting compound going forward.

I agree. What I love about the ASH meeting and these recaps with my colleagues is that I am learning as we speak. I have recently learned—within the last few seconds—that APR-246 is going to be called eprenetapopt.

I am glad you said that and not me because I am sure I would have mispronounced it.

Use of APR-246 and Oral HMAs in AML

One of the issues about transplant is how we get patients with AML [acute myeloid leukemia] to transplant. Is transplant the end of the road, or should we be thinking about maintenance for many of our patients, especially those with higher-risk disease? At last year’s ASH [American Society of Hematology Annual Meeting] and ASCO [American Society of Clinical Oncology Annual Meeting], there was an update of the study led by Jeff Lancet, of CPX-351, the liposomal daunorubicin-cytarabine formulation vs standard 7+3 chemotherapy in patients with AML, with myelodysplasia-related changes and therapy-related AML. The 5-year update showed continued improvement in overall survival for the patients who were randomly assigned to CPX-351 [cytarabine, daunorubicin].

What was most impressive in this group is that, at 5 years, if you landmark the survival from the time of transplant, that is when the benefit was most pronounced with 40% of patients still alive compared with 20% in the 7+3 chemotherapy arm, and most of those patients had undergone transplant. The subset analysis and the landmark analysis from this phase 3 study suggested that receiving CPX-351 [cytarabine, daunorubicin] for some reason led to better outcomes postallogeneic stem cell transplantation for these high-risk patients.

Eunice, I want to turn to ask you about patients who you think are going to go to transplant with this high-risk disease. Do you consider CPX-351 [cytarabine, daunorubicin] for them, or are you moving on to using HMA [hypomethylating agent]-venetoclax combinations, which have also been shown to be useful as a bridge to transplant from the phase 1b data that were presented by Keith Pratz? Eunice?

This is another hotly debated topic, and I have colleagues in my service at Roswell Park Comprehensive Cancer Center that fall on both sides of that argument. My preference is that, if there is a patient who is younger and fit, has a poor prognosis, complex karyotype, and therapy-related AML MRC [myelodysplastic-related changes], who is able to tolerate therapy based on their comorbidities and overall outlook in an intensive regimen, my inclination is to offer CPX-351 [cytarabine, daunorubicin].

It is rare in a leukemia meeting to see 5-year overall survival for any study. Most of our studies, particularly those in the relapsed/refractory setting and even in the up-front setting, only have 2 or 3 years of follow-up because everybody is dead at that time. To have 5-year data showing a significant percentage and an improvement, as well as the compelling landmark data post-transplant, that gives you some hope that, if you can take a patient to CPX-351 [cytarabine, daunorubicin] and then take them to a transplant, you can tell them that there is a 40% 5-year survival. That is remarkable even though the numbers are small.

There are individuals, however, for whom the toxicity of induction chemotherapy, whether it’s in a liposomal formulation or just standard 7+3 chemotherapy, may be prohibitive. There are patients who go into induction looking great, then they get septic, go to the unit, get on pressors, and almost die, and they come on out. With those patients, even though we would love to take them to transplant with Corey Cutler’s group particularly, we would hesitate. There are some patients in whom I now use oral azacitidine, CC-486, as an alternative to transplant, because I feel they would not tolerate a transplant well. There are those who, even in the up-front setting, do not look that great, and you know this person has bad disease—save, for example, complex karyotype 

You know that for 7+3 chemotherapy, even liposomal 7+3 chemotherapy, the subgroup analysis by Coleman Lindsley and colleagues at Dana-Farber Cancer Institute with Dr Cutler says that patients who have 

-mutant disease do not necessarily benefit in terms of overall survival from a CPX-351 [cytarabine, daunorubicin] induction regimen. There are those patients for whom we utilize that high response rate and tolerability of what I would call an intermediate-dose induction of venetoclax-azacitidine to get to transplant.

Keith Pratz and colleagues at Perelman Center for Advanced Medicine presented a small subset analysis of about 10% of patients receiving venetoclax-azacitidine in the phase 1b trial and in another clinical setting, but that 10% is about 30 patients. They showed that, in that small subset of patients who went to transplant, there were high response rates with subsequent transplant. That was a small subset as I said, and the initial eligibility for the phase 1 trial, as for many of these trials, is that you had to be unfit for transplantation or intensive chemotherapy at the time that you were enrolled in the trial. It raises the question that those patients may have been those who were sick from their disease, so they were clinically judged by the physician not well enough to undergo intensive chemotherapy, but with the achievement of two-thirds of those patients going into CR [complete remission], they improved functionally enough to go to transplant. There are a subset of patients for whom we want the opportunity to do that, so we do not exclude transplant as an option depending on how those individuals do with up-front venetoclax-azacitidine.

Eunice, you touched on a number of important topics, so I want to come back to some of them because they warrant being fleshed out a bit. Sasha, I am going to put you on the back burner for a second because I am going to come back to you to discuss 

 mutations and APR-246, which has been shown to have activity in this subset of patients.

Role of Transplant in AML

A lot of what we are talking about here in terms of barriers to transplant is the toxicity, especially in some of our older patients. I know the transplant community has been working hard at trying to improve a number of the toxicities that are seen in terms of time to engraftment and graft-vs-host disease. Along those lines, this year [2020], there have been presentations and publications regarding a new drug, or cellular therapy, I should say: omidubicel. This is something I know nothing about, so Corey, can you educate these leukemia doctors who do not do transplant about this?

Sure. Omidubicel is a mouthful, so I like to use NiCord, which is the commercial name for this product. It is a modified umbilical cord product that we are using in transplantation on an experimental basis. We have not seen the full data set from a large randomized trial that was completed, but there has been a release of top-line data that suggested that this product will or has met its primary efficacy end points in a trial. This is a product with which we take umbilical cord blood, and we mechanically separate the CD34-positive hematopoietic progenitors from the CD34-negative fraction. The CD34-negative fraction is re-cryopreserved, and the CD34-positive stem cells are expanded in a somewhat proprietary fashion by the company Gamida Cell. After an expansion has been completed, both the CD34-positive expanded stem cells and the CD34-negative fraction, comprised largely of T cells, are infused after conditioning is completed.

The trial was a randomized attempt to look at the efficacy of this expanded or modified cord blood product against a standard cord blood transplant, which could either be a single-cord or a double-cord transplant, and we use double-cord transplants at our institution, Dana-Farber Cancer Institute. The trial was led by Mitch Horwitz, MD, from your institution, Duke University School of Medicine, and the top-line data suggested that the time to neutrophil engraftment was dramatically and statistically reduced in the NiCord [omidubicel] group down to 12 days, which is the same as any peripheral blood stem cell product. The rate of engraftment was higher in the modified product, and we expect that early things like early transplant-related morbidity, days in hospital, infection rates, and all those important end points that go along with engraftment will be significantly better in the NiCord, or omidubicel, arm. We are anxiously awaiting the full data set there. That data will likely be presented at the Transplant & Cellular Therapy meetings in February in 2021.

There was a second abstract at ASH [the American Society of Hematology 2020 annual meeting], which looked at this product in severe aplastic anemia. It was a small study: only 8 patients were reported, the first 3 of whom received both the omidubicel product with haploidentical stem cells, as a safety net if you will, against failure to engraftment. There were 5 subjects who received this product alone, and my understanding is that all 5 engrafted. There was 1 subject of the 8 who had late graft failure, but 7 of 8 subjects were reported as alive and well at the ASH presentation recently.

This is an important advancement. This will likely become the first manipulated cellular product to be approved in stem cell transplantation. It remains to be seen how it will be used in the real-world setting, but it is exciting that the umbilical cord transplant field is moving forward.

Thank you. Yes, it is my pleasure to move to Duke and work down the hall from Mitch Horwitz. He is a great guy, and he has done well in leading this trial. He also led the BMT CTN trial of reduced intensity vs myeloablative transplant. That was a negative trial, but it led to important work that we discussed from Chris Hourigan, MD, PhD.

Use of Omidubicel Therapy in Hematologic Malignancies

This has been an amazing discussion. There is so much more to discuss now in AML [acute myeloid leukemia]; the last 3 years have been a whirlwind of new therapies. What I would summarize of our discussion so far is that we still have a whole lot to learn about how to use all of these drugs and a whole lot to learn about how to use some of our methods of detecting measurable residual disease.

I want to turn to an important topic for our patients with myeloid neoplasm, and I know it is a bit outside the scope of AML, but we have Corey Cutler MD, MPH, FRCPC, here today, and Corey presented what is one of the most important practice-changing or educating presentations at ASH [the American Society of Hematology 2020 annual meeting]. It was his oral presentation of the BMT CTN 1102 study looking at reduced intensity allogeneic transplant vs the use of hypomethylating agents [HMAs] in patients with higher-risk MDS [myelodysplastic syndrome]. This is incredibly important because CMS [Centers for Medicare & Medicaid Services] has not been covering allogeneic transplant for our older patients with MDS, and CMS asked for this study to be done. Corey, you and the BMT CTN pulled it off, and I am glad that you are here to discuss it with us today.

Thanks for having me. I would like to start by saying how refreshing it is to hear a bunch of leukemia investigators talk so favorably about transplantation by and large. I also believe that the CTN 1102 trial was an important study. We, at the Dana-Farber Cancer Institute, looked at nearly 400 subjects, and we allocated them to donor or no-donor assignment based on the presence of whether they had an HLA [human leukocyte antigen]-matched sibling or HLA-matched unrelated donor. These were all individuals above the age of 50 but below 75 years of age who had intermediate-2 or high-risk MDS at any point in their disease course.

Subjects were treated according to whatever local standard was considered in their best interest at their center, so we did not specify what type of low-intensity transplant to perform or what regimen to use. Similarly, we did not specify what regimen of hypomethylating therapy or other supportive measures they could receive. It was important that we noted that, at the end of 3 years, the median outcome in subjects who were allocated to the donor arm was about 21% higher than subjects who had no donor. There was an almost 48% 3-year overall survival in the donor group, which was significantly better. The leukemia-free survival outcomes matched that, and we looked at an intent-to-treat analysis where we took subjects in the no-donor arm who underwent alternative donor transplant out, and we excluded the subjects in the donor arm who did not undergo transplant, and the results were even more striking. We believe that it was a practice-changing therapy. We think that this is going to solidify the role of allogeneic transplant in transplant-eligible older individuals with high-risk MDS, and we believe that CMS will reconsider its decision on payment for this procedure moving forward.

Corey, one of the interesting things I found about the assessment was that the benefit in terms of survival was there regardless of whether the patient received HMA or their response to HMA. That caught me by surprise because I have always been told to give the patient azacitidine, get that blast count below my magic number, and then do a reduced intensity transplant. Do you want to comment on that?

We looked at subgroups based on whether subjects had received HMA and whether they were responsive to HMA therapy in the past, and the benefit was seen across the board. There were slightly different magnitudes depending on the subject’s prior responsiveness to HMA, but the benefit was seen across the board. Importantly, there were probably not a huge proportion of patients in this trial who had already exhausted many of their treatment options and were using transplant as a therapy of last resort. That is an important consideration here, and one of the main messages from the trial is that transplant should not be the last resort. We would like to meet transplant-eligible patients early in their disease course so that we can do the best donor search that we can and be ready to move to transplant when the patient is medically ready.

You bring up an important point there, which is the transplant-eligible patient. For the doctors in the community, what do you mean by that? Are these patients 71 years old, 78 years old? What about age or comorbidities? How are they supposed to know what you are looking for?

We no longer use age as a fixed cutoff for transplant eligibility. A fit patient who is 71, 72, or 73 years of age is certainly somebody we would consider for transplantation. We look at medical comorbidity as an important factor to determine whether someone is transplant eligible. Measures of geriatric assessments are important in these individuals, but we have transplanted individuals up into their late 70s, but patients in their low 70s, particularly in 2020, are very much fair game for who might be eligible for a reduced intensity transplant. As we get better at matching and as we get better at preventing and treating graft-vs-host disease, transplant outcomes are clearly going up. Individuals at advanced age are not necessarily excluded. Quite frankly, if the community-based physician is not sure, then have that patient come to the transplant center to have a meaningful discussion with the transplant team to learn about the potential downsides of transplant. What are the risks? What are the potential complications? Let the patient decide what is right for them.

Those are good points. Sasha [Alexander], Eunice, do you agree with early referral for transplant for patients with high-risk MDS?

I agree with that. Only a proportion of my patients decide to go to transplant, and that is interesting because, for most patients, even my own transplant team will say that, if you have a patient with high-risk MDS, they do not have acute leukemia, so we do not have to transplant them right away. They say, “Why don’t you go ahead and give them a few rounds of azacitidine, see how they do, and then get back to us?” I’ll say, “This person has like a 

, I don’t know whether they’re going to do great.” We get a little pushback from that saying, “Go ahead and treat them, and then when you get around to it, we’ll do transplant down the line.” Early referral is great because a lot of people do not do that, and we should be pushing our transplant colleagues to say, “It doesn’t matter if they respond to HMA or not. I don’t have to give them 4 to 6 rounds of HMA, so maybe you should just take them now.” I have had those patients who develop complications and never get to 4 or 6 rounds, so that is an important message. The CMS thing has been a deterrent for some of our older patients and their ability to get transplants.

In my practice, I definitely use HMA therapy as a bridge to transplantation, and anyone with higher-risk MDS who is being evaluated for transplant should be receiving some form of therapy until the time of transplant has come. I generally do not stand on ceremony, waiting for someone to see 4 or 6 cycles. Give them a round or 2 while we are doing our search. If they are doing great on the HMA therapy, and the blast count is coming down, perhaps give them 1 or 2 more rounds. If things are not going as planned, and the blasts are not coming down or if the patient is not tolerating HMA therapy well, then it might be the right time to move right to transplant then.

status. There are certainly patients in whom reduced intensity transplant is not appropriate, and 

 status might be one of those factors that one has to take into consideration. For someone with borderline comorbidity and a 

 mutation, perhaps that is someone in whom transplant is not necessarily the right decision. Again, it is a measure of balancing patient expectations and all sorts of other factors. It is always worth having a conversation.

That is an important part of this entire discussion. Have the patient decide: they need to have a caregiver, and they need to evaluate their own therapeutic goals for where they are in their life. This is not something that happens in a 5-minute or 10-minute conversation, and it may not be done in 1 clinic visit, but it is an incredibly important part of the entire discussion. I agree with you. This is a discussion that I often have with patients as I am giving them azacitidine as to when I will refer them to transplant, and I try to encourage that early in the process.

BMT CTN 1102 Study in High-Risk MDS

I want to move on; I want to get to some big investigational agents that are important. Before getting there, I will mention that there were a number of studies looking at BCL2 inhibition with venetoclax in combination with intensive chemotherapies like CPX-351 [cytarabine and daunorubicin] and idarubicin-FLAG [fludarabine, cytarabine, granulocyte-colony stimulating factor], and the results of a study from The University of Texas MD Anderson Cancer Center of cladribine and low-dose cytarabine. These were safety studies. It is important to point out that myelosuppression appeared to be the biggest safety signal, so outside of clinical trials, these things are not yet recommended, but more study is required. We will hopefully see that BCL2 inhibition can improve outcomes for patients getting intensive chemotherapy as well.

I want to turn to a couple of important investigational agents, and one that I am really excited about, and I think others are too, has data that Eunice presented at ASH [the American Society of Hematology 2020 annual meeting] on the menin inhibitors that may or should have activity in 

-rearranged AMLs [acute myeloid leukemias], as well as nucleophosmin [

]-mutated AML. Would you tell us about the menin inhibitor that you were studying with your colleagues?

Sure. On behalf of my colleagues, at Roswell Park Comprehensive Cancer Center, I presented some preliminary data from a first-in-human phase 1b study of KO-539, which is a novel menin inhibitor being developed by Kura Oncology, Inc. As you know, about 5% to 10% of acute leukemias with AML and ALL [acute lymphocytic leukemia] are characterized by rearrangement in the 

gene. Those particular leukemias are largely characterized by secondary AMLs, therapy-related AMLs, and pediatric ALLs. There also is a subset, about a third of AMLs as you know, that are characterized by 

 mutations, and those can confer a favorable prognosis in some settings. In other settings, it is something that, to date, we have not been able to target successfully, and for that reason, it is not considered one of our actionable mutations per se.

The menin inhibitors work by targeting the menin interaction with the 

 epigenome complex, and that complex is responsible for regulation and transcription of promoters that lead to inhibition of differentiation, and preservation or halting of the myeloid blasts in an undifferentiated state. By targeting menin and targeting that interaction, we may be able to restore differentiation to myeloid blasts, thereby leading to improved outcomes.

This was a first-in-human study. Cohorts were studied anywhere from 50, 100, 200, to 400 mg. Based on preclinical data and some in-class data, there was some initial concern about EKG [electrocardiogram] prolongation, QTc [corrected QT interval] specifically, as well as interactions with the azole antifungal drugs, the CYP3A4 inhibitors, as we saw with venetoclax. To date, in 12 patients examined from 50 mg all the way to 400 mg, there have been no treatment-related adverse events of consequence. No patients have stopped therapy, there has been no QTc prolongation, and there appears to be evidence of early clinical activity in 6 out of 8 patients treated up to 400 mg of drug.

Interestingly, on the phase 1 dose escalation portion, as is common with these studies, we enrolled relapsed and refractory patients as a very-poor subset. These were patients that had between 2 to 7 prior rounds of therapy, and they were agnostic of the mutation. There were 2 CRs [complete responses] that were obtained in those early patients: 1 was MRD [minimal residual disease] positive, 1 was MRD negative, 1 of those patients had an 

 mutation, and the other did not. There also was activity stabilization of disease, a morphologic leukemia-free state, and decreased Hydrea [hydroxyurea] requirements in other patients, one of whom had a 

 rearrangement. These data, though early, suggest tolerability and early signs of some activity even in a patient who had 7 prior lines of therapy.

We are enthusiastic, cautiously. This is a small number of patients, and it is in the early days. As we all know, a few responses in a few patients does not a blockbuster drug make, but it is an interesting mechanism of action. The fact that we are seeing it across mutations suggests that there may be efficacy outside of these 2 molecular subsets. However, if we were to…on molecular subsets, that would be exciting because there is not yet a precision medicine approach for those particular disease subtypes.

What I thought was interesting about your presentation was that the 2 deepest responses were in patients who got azole antifungal agents and CYP3A4 inhibitors with the study drug, but you did not see increased toxicity either.

Right. We do not know whether the azole antifungal agents, as we have seen with gilteritinib, would enhance the levels. We saw activity regardless. We are certainly not excluding the use of azole antifungals, but that is certainly encouraging, and is helpful because a lot of us use azole antifungals in our routine practice.

Thank you. There were 2 other targeted therapies that were discussed at ASH. I will mention one of them briefly, and that is the retinoic acid receptor-alpha agonist, which is from Syros Pharmaceuticals. The generic name that I know it by is tamibarotene, which I believe is approved in Japan and has been evaluated in acute promyelocytic leukemia. In patients with AML who have retinoic acid receptor present on a biomarker assay, there was a reasonable and significant response rate, I would say, with the combination of tamibarotene with azacitidine in AML.

The update I want to leave this section with is with magrolimab. Magrolimab is the first-in-class anti-CD47 monoclonal antibody. CD47 is known as the “don’t eat me” signal for the innate immune system, and the idea here is that, by blocking CD47, you block the signal that tells the macrophage not to eat a cell. On top of that, the Fc portion of magrolimab is active, so by binding to Fc receptors on the macrophage, you get an “eat me” signal, so you would anticipate that there would be activity of an anti-CD47 antibody. You would also anticipate some on-target toxicity. Since CD47 is expressed on red cells, you get expected anemia, and the investigators figured out how to dose magrolimab to ameliorate this expected anemia.

The presentation here by Dave Sallman, MD, was on 52 patients with AML with a median age of 73. They included two-thirds who had poor-risk cytogenetics and two-thirds who had 

 mutations. Let me focus on those patients with 

-mutated AML. There were 21 patients with an objective response rate of 71%, including 10 of the 21, 48%, having a complete remission, and a median duration of response was 9.9 months, which is longer than might be expected otherwise. Of course, you cannot compare between different data sets, but there was a median overall survival of 13 months in those patients, which is pretty remarkable. They also looked at the leukemic stem cell, which also expresses CD47, and they found that the leukemic stem cell was eliminated in 71% of the patients treated with magrolimab/azacitidine. The development of magrolimab, as well as other anti-CD47 antibodies, is ongoing, and we look forward to more data coming from phase 3 studies of magrolimab as well as phase 1 studies of second-generation anti-CD47 antibodies.

Novel Targets and Biomarkers in AML

I am going to bounce back to Sasha [Alexander] to discuss something about 

 mutations, for which I have not been coming to him. Sasha, I don’t think of you as just the 

 guy, but I treat leukemias that have mutations other than 

That’s when somebody else is out of town, right?

It’s the left pinkie leukemia doctor and the right pinkie leukemia doctor.

I am going to put you on the spot. I am sure that you are up to the challenge, though. We have learned from the phase 1 studies of ivosidenib and enasidenib in patients with 

-mutated, treatment-naïve AML [acute myeloid leukemia] in small subsets that there is activity of those inhibitors. We have also learned from either phase 1b or randomized phase 2 studies of higher response rates of azacitidine with ivosidenib or azacitidine with enasidenib in patients with 

-mutated, treatment-naïve AML. There are high response rates, but we also saw the presentation by Dan Pollyea MD, MS, at ASH [the American Society of Hematology 2020 annual meeting] looking at the activity of venetoclax with azacitidine in patients with 

mutations, which showed high response rates and impressively high survival.

My question to you is this: what should a clinician do? Ivosidenib is now approved for patients with previously untreated 

-mutated AML. You might be able to get enasidenib for your patient with 

 mutations, but we have azacitidine/venetoclax. Should you be doing mutational analysis to help guide choice, or do you start with azacitidine/venetoclax and use IDH inhibitors in the relapsed/refractory setting? What do you advise?

I can tell you what I do. There really is no study that tells us what we should do. What I generally do is this: if I think the patient is up to the treatment, and the treatment is exactly as Eunice has nicely described, then I give patients azacitidine plus venetoclax, and I expect a good response in a patient who has an 

 mutation. It has a high response rate, and it is quite durable. But it is not uncommon that we run into issues on subsequent cycles, where patients can get cytopenia, or they might have the tolerability issues or trouble getting in for the number of doses of azacitidine that they need to get, and they want an easier option at that point. When I am thinking about if we want to create a treatment break, if we want to move to something different, or if they should have progression, that is when I am more typically looking to give ivosidenib. I recognize that I can give that in the frontline setting, but there are few patients for whom I would choose it over an HMA [hypomethylating agent] plus venetoclax as a frontline option.

The population that might be most interesting is those who have had MPNs [myeloproliferative neoplasms] and progressed to AML. They have had high response rates to IDH inhibitors, and they were not studied at all in the VIALE-A trial nor the prior venetoclax development. Those might be good patients for whom we may look at an IDH inhibitor because they can have surprisingly good responses and durability of response in that context. Those are patients who may benefit from an IDH-targeted approach. Across the board, I have not used mutational analysis to guide whether I give a one or another regimen in the unfit group that is older. I have typically been using HMA plus venetoclax there.

The one place where I have considered ivosidenib and azacitidine is in someone who already comes in ill with infection, and I do not think I can get through a prolonged period of neutropenia. One of the interesting parts of Courtney DiNardo’s MD, MSCE, presentation at EHA [the European Hematology Association 2020 annual meeting] was that the blood counts, specifically the neutrophil counts, seem to be getting better in patients during their first cycle. It might be a place where you can consider ivosidenib with azacitidine, but I agree with you. I start in the labeled indication of azacitidine/venetoclax and then use enasidenib and ivosidenib in their labeled indications for relapsed/refractory disease.

IDH1/2-Mutated Treatment-Naïve AML

I want to move things around. Before I come back to a targeted therapy against the 

 mutations, I want to talk about inhibition of BCL2 in AML [acute myeloid leukemia]. We will all agree that the VIALE-A study has been practice-changing, at least in the United States. As a top-line review of this study, before we get into some specific questions, I will start by saying that the VIALE-A study was a study of treatment-naïve patients with AML who were either 75 years of age or older or had a comorbidity that precluded intensive chemotherapy. In this study, azacitidine with venetoclax was compared with azacitidine with placebo. The primary end point of the study was reached: There was an improvement in median survival from 10 months with placebo-azacitidine, which is similar to what was seen in the QUAZAR AML-001 study, to almost 15 months with azacitidine-venetoclax. For me, 1 of the more impressive things about those Kaplan-Meier curves is that, with follow-up ongoing, the curves have not come together at least by 24 months, which happened in the QUAZAR AML-001 study, where azacitidine was compared with conventional care regimens. There was a 34% reduction in the risk of mortality, and the other benefits that were seen were higher response rates and higher rates of transfusion independence with azacitidine-venetoclax.

With that as a background, we are all using this regimen, but I want to turn to Eunice to talk through some practical issues, specifically around monitoring and risk of tumor lysis syndrome, antifungal prophylaxis, and how to manage cytopenia. These are the important issues that we need to convey to our colleagues who may not see as many patients with AML as we do. Eunice?

I would be happy to. When we decide to administer venetoclax-azacitidine for an older or unfit individual, we have to take into consideration the management of toxicities. The first question that comes up is whether the patient is eligible to be treated in the inpatient setting vs the outpatient setting. Unlike an HMA [hypomethylating agent] alone or azacitidine, the combination of venetoclax and azacitidine is myelosuppressive: 70% to 80% of individuals will develop neutropenia, and others will develop significant degrees of thrombocytopenia. That is going to require these individuals to be closely monitored not only during the first week of administration of both agents but also for 2 to 3 weeks following that.

There are some guidelines that have been published looking at the requirements that are needed to support an individual in the outpatient setting. Those include the ability to monitor the patient or see the patient on a daily basis or at least 3 times a week to check laboratories and manage tumor lysis syndrome, which occurs with initial dose escalation, with IV [intravenous] fluids and tumor lysis monitoring labs as well as medications. They also include the need for very frequent red blood cell and platelet transfusions: at least 2 to 3 times a week. In fact, those requirements are difficult to achieve in many community settings; even in academic settings we are not necessarily set up to do that. The NCCN [National Comprehensive Cancer Network] Guidelines in this newly revised supportive care regimen suggest at least hospitalizing these individuals potentially for the first week of treatment as you dose escalate the venetoclax, given all those requirements for tumor lysis monitoring, etc.

In terms of subsequent management, we always, at our facility at Roswell Park Comprehensive Cancer Center, administer antifungal medications and CYP3A inhibitors—posaconazole is our preferred agent. We then initiate that in the setting of expected neutropenia with these patients, we dose reduce according to the azole drug and the product insert. There have been several studies of venetoclax and several questions from all the speakers at the ASH [American Society of Hematology] Annual Meeting 2020 about the concomitant use of azole antifungals, and I have not heard of anybody who has seen a significant difference in the efficacy of the agents based on the use or nonuse of azole antifungals. That is based on your institutional practice, and there is some geographical variation in that as well.

In terms of adverse-event monitoring in the second and third weeks, if you are able to maintain that type of regimen, we would recommend that you do so either in the inpatient setting or the outpatient setting. Major causes of mortality were pneumonia, sepsis, and neutropenic fever. In the VIALE-A trial, those were low in the single-digit range; however, I have been told in the community that, given the lack of access to those resources, it could be as high as 10% to 40%. It is important to recognize that this is not azacitidine alone. These are patients who are going to be severely myelosuppressed. I have had some patients in the community being started on this regimen showing up in the ER [emergency department] with a white blood cell count of 0 and a platelet count of 3 per mm3. We would strongly advise close management. At our facility, we offer to admit the patients for the first cycle to get them through their first day 21 and day 28, start the second cycle, and transition them back to the community.

I ask that individuals consult closely with an academic center for guidance. We have had physicians call us every few days to say, “The platelet count is now 10 per mm3. What should we do?” or “It’s going back up again.” If patients achieve sufficient cytoreduction on day 21 or day 28 bone marrow biopsy, that is like the day 14 bone marrow biopsy with 7+3 chemotherapy: We can use that bone marrow biopsy to hold venetoclax for ANCs [absolute neutrophil counts] less than 500 per mm3. We administer growth factors, we transition them to outpatient, then start the next cycle with truncation of subsequent venetoclax and azacitidine dosing based on cytoreduction that we are getting from the cytopenia. I hope that addressed all 4 of the questions that you asked, Harry. I gave a bit of time left for somebody else to speak for this section.

Eunice, that was wonderful. I appreciate the detail that you went into because here is the bottom line: HMA-venetoclax is able to improve the survival of older and infirm patients with AML, but it was done in the context of a clinical trial with specific rules on how to handle drug-drug interactions, tumor lysis syndrome, and myelosuppression. If we do not follow the supportive care in the clinical trial, what we have learned since is that we are not going to be able to reproduce those regimens. In fact, there are some real-world data out there that suggest that many patients are not receiving as many cycles of HMA-venetoclax as in the clinical trial, suggesting to me that clinicians may be backing off this regimen prematurely because of apparent or presumed toxicities of the regimen and not knowing how to manage it.

I agree with that completely. I could not agree more.

I appreciate you taking the time to do that.

BCL2 Inhibition in AML: VIALE-A Study

Before we leave the topic of FLT3 inhibitors, I want to talk about the difference between type 1 and type 2 inhibitors. A type 1 inhibitor is a second-generation drug like gilteritinib that inhibits both the TKD and the ITD mutations, and a type 2 inhibitor such as quizartinib inhibits only the ITD, not the TKD. There has been a lot of discussion about the mechanisms of resistance with those type 2 inhibitors, where you might see TKD mutations coming out, but there are also mutations that occur at the time of progression after gilteritinib with 

Sasha, you presented on a comparison of these 2, and I want your summary of whether you think there is room for both a type 1 and type 2 second-generation FLT3 inhibitor. Sasha?

Just to clarify, I will say something. The presentation we did was a poster that largely looked at the question of how active gilteritinib was in the population studied in the phase 3 quizartinib study. It did not compare gilteritinib with quizartinib, though realistically, if you look at the data sets, you can draw your own conclusions. You have to be careful with cross-study comparisons when you are looking at 2 different data sets. I would not suggest that this is what we were trying to do.

We know that the QuANTUM-R study and the ADMIRAL study, which are phase 3 evaluations of a second-generation FLT3 inhibitor vs salvage chemotherapy, were similar in design. The 2 drugs are similar in terms of how they work, their activity, response rates, and even the survival. At the end of the day, they are more similar than they are different. There are improvements in response, and there are improvements in survival with each drug compared with chemotherapy. The reason we did this analysis was to ask if the differences in terms of the survival benefit seen in the ADMIRAL and QuANTUM-R trials were because of the populations of the studies or in any way the differences in the drugs. I do not think that, at the end of the day, we can say that because it is not a direct comparison of the drugs. Gilteritinib is active in patients who would have met eligibility for the QuANTUM-R trial: who were higher risk than those on the ADMIRAL trial because they had to relapse within 6 months of first remission, and they could not have a TKD mutation as their only 

 ITD mutations, and the response rates were largely overlapping in terms of the 2 drugs. The survival was 10 months in the gilteritinib arm of the ADMIRAL trial; that would have matched that of the QuANTUM-R trial, and the differences in adverse effects were relatively small: more QT prolongation with quizartinib, more LFT [liver function test] abnormalities with gilteritinib. There are some differences in terms of duration of response and time to progression. The full count recovery is more common with gilteritinib, but there is room for both if we could have access to both.

In Japan, both drugs are approved, and I am a bit envious of that scenario. As you know, the ODAC [Oncologic Drugs Advisory Committee] decided not to recommend approval for quizartinib, so its approval process in the relapsed/refractory setting was halted there. The drug has undergone a frontline evaluation, 7+3 chemotherapy plus quizartinib vs placebo, which has completed enrollment. That is the QuANTUM-First study, and when that reads out, we will know whether that study meets its primary end point, which has been modified to be overall survival. It may take a bit longer to get that readout.

Type 1/2 FLT3 Inhibitors in AML

I want to use that as a quick segue away from 

, and now talk about combinations. Eunice, I am going to turn to you for that. What do you think about the data presented from The University of Texas MD Anderson Cancer Center of gilteritinib with venetoclax, trying to combine both of these targeted approaches?

This trial was also led by Sasha, and it was the dose-expansion cohort of a phase 1 study where they initially looked at the tolerability and safety, and they are now looking at the efficacy in patients with relapsed/refractory disease. A small proportion of those patients who had gone on study had failed either venetoclax alone or gilteritinib alone: about 20% of patients. The fact that you could have response rates well over 80% looking at CR [complete response], Cri [CR with incomplete count recovery], and CRh [complete response with partial hematologic recovery] in those individuals with the combination of venetoclax and gilteritinib was highly promising. This is something. Some of us are so impressed with these results that we are starting to consider using that combination in the off-label setting for patients with 

-mutant disease that has recurred or come back particularly after a venetoclax-azacitidine treatment. Even though Sasha says that would be his preferred regimen at the time of recurrence with 

-mutant disease, instead of just using the gilteritinib alone, we are continuing with the venetoclax as well.

That approach looks very promising for a few reasons. No. 1, it overcomes different mechanisms of resistance. As you know, you can get resistance developing to gilteritinib primarily through 

 mutations, and you can get resistance to venetoclax based on the development of 

 mutations. Combining the 2 seems to make a lot of sense from a biological point of view, and it overcomes cross-mechanisms of resistance. Patients also like it because it is a completely oral regimen. We have to say that the tolerability and dosing to minimize myelosuppression while preserving extremely high response rate is an attractive option, mostly because the patients who have gone on a bunch of therapy with either the VIALE-A trial or azacitidine-based therapy are usually unfit patients. These are not patients whom you would be asking to undergo a salvage treatment with MEC [mitoxantrone, etoposide, cytarabine] or FLAG [fludarabine, high-dose cytarabine, GCSF]. That combination is extremely promising. I know there is discussion about potentially moving that to the up-front setting and exploring that in a triplet regimen. That also suggests that it is feasible to give dual targeted therapy, which is also an important concept. Most of the combinatory studies at 2020 ASH [American Society of Hematology] Annual Meeting were combinations; for example, venetoclax with low-dose chemotherapy, venetoclax with high-dose chemotherapy, and venetoclax with a TKI [tyrosine kinase inhibitor]. The fact that we can combine venetoclax with a targeted TKI is valuable information, and it is very promising.

Role of Dual Targeted Therapy in AML

Before we get to the combination, let’s talk about sequencing because we now have more data looking at sequential use of FLT3 inhibitors or a second-generation drug like gilteritinib following the first-generation drugs, midostaurin/sorafenib. I know you presented on this, Sasha, at the 2020 ASH [American Society of Hematology] Annual Meeting. Do you want to summarize some of that data?

 I presented data that came from the ADMIRAL study and the CHRYSALIS study for the phase 1/2/3 development of gilteritinib, recognizing that the phase 1/2 study was designed for anyone with relapsed and refractory disease, the vast majority of whom were 

 mutated, but it did not have any restrictions in terms of prior therapy. About a quarter of the patients on that study had a prior FLT3 inhibitor. By the time gilteritinib was brought to the phase 3 setting, midostaurin was approved in many places, and sorafenib was commonly used post-transplant, so there were patients who were treated with these drugs, but you could not have had prior salvage therapy when you went on the ADMIRAL study. In general, there were relatively few people who had had a prior FLT3 inhibitor based on when the study enrolled. Only 12% of patients in the ADMIRAL trial had a prior FLT3 inhibitor, and the question comes up: should we be giving gilteritinib in somebody who has progressed after a regimen containing midostaurin with sorafenib now that these are commonly used in frontline therapy, either with induction and consolidation or post-transplant.

We did not have a lot of data to guide that from what we got out of the ADMIRAL trial, so we pooled the analysis of those 2 studies, the phase 1/2 CHRYSALIS trial and the phase 3 ADMIRAL trial, among the patients treated who had had prior FLT3 inhibitor, either midostaurin or sorafenib. We then looked at the outcomes of patients who had not had that on both of the arms for the ADMIRAL study—because there was a chemotherapy arm—what we basically found was this: the response rates to gilteritinib were still quite robust if you had prior midostaurin or sorafenib without much of a difference between the 2 of them. There was not a finding of pan-resistance if you had progressed after prior therapy. The response rates were a bit lower, more like about 40% composite CR [complete response] rate rather than 50%, but both of these were certainly better than the chemotherapy arm comparator. Even when we did a statistical comparison of the survival of those treated with gilteritinib on the gilteritinib TKI [tyrosine kinase inhibitor] arm vs the placebo arm, that was still highly statistically significantly better.

We can at least say that, when we looked at patients who had had prior FLT3 inhibitor midostaurin or sorafenib, responses were fairly comparable, and survival may be a bit lower than that seen in patients who had not had a prior FLT3 inhibitor, but it is still superior to alternatives. I would not recommend anything other than what you would ordinarily do for these patients: Use the data that say that gilteritinib is a superior option than salvage chemotherapy. It does not change the directive to use gilteritinib as the preferred salvage agent in patients with relapsed and refractory disease.

At this year’s meeting, Keith Pratz from your institution, the University of Pennsylvania Perelman School of Medicine, presented data from the phase 1b study of gilteritinib in combination with standard intensive chemotherapy, 7+3 and high-dose cytarabine, with a high response rate of 80%. It was basically a study that was large enough to say that this can be done safely.

What we are getting at here is sequencing. Should we start with a first-generation or a second-generation drug, first? We do not know. The PrECOG study that is being led by Selina Luger and Keith Pratz as well will be looking at intensive chemotherapy with either midostaurin or with gilteritinib in previously untreated patients with 

 mutations. We have to wait for the results of that type of trial. A similar study with crenolanib vs midostaurin is also ongoing at this point. We await the results of those studies that look at the benefit of a type of a second-generation drug in combination with chemotherapy vs the first-generation drugs.

Sequencing of FLT3 Inhibitors in AML

Eunice, why don’t you discuss the data that you presented on gilteritinib?

At the 2020 ASH [American Society of Hematology] Annual Meeting, we at Roswell Park Comprehensive Cancer Center presented the updated safety cohort data from the LACEWING study, which is a phase 3 randomized controlled trial of gilteritinib plus azacitidine vs azacitidine alone in individuals with AML [acute myeloid leukemia], 

 mutant, who are considered unfit for intensive chemotherapy.

The original trial was a 3-arm cohort trial in which patients with FLT3-mutated AML were unfit, and they were supposed to be randomized to receive gilteritinib alone, azacitidine alone, or the combination approach. Patients were to be randomized after a lead-in safety cohort to determine the best dose of gilteritinib, either 80 or 120 mg. Data presented at the meeting included the safety cohort, of which there were 15 patients. The dose of gilteritinib was determined to be 120 mg. Of those 15 patients, some of whom got 80 mg and some of whom got 120 mg, 10 of 15 had a response. There was about a 33% CR [complete response] rate and a total CR/CRc [composite CR] rate of 67%, and the median overall survival with the long follow-up was 10.8 months, with 1 patient making it all the way to 36 months on therapy.

Based on that result, we have moved into the randomized component. There was a protocol amendment in which the company decided not to enroll patients further on the gilteritinib-alone arm, and that was based on data suggesting that there was potentially a low response rate with monotherapy and increased risk of developing further resistance down the line, as well as the data from studies like the VIALE-A trial suggesting that combinatorial approaches might be better. That study is about half accrued; it is a trial in progress, so they are anticipating to finish accrual within the next year or so and hope to have future results at another meeting. What I would like to highlight is the high response rates, which are similar to the response rates they were seeing with the VIALE-A trial with about two-thirds of patients achieving a CR/CRc. It is a well-tolerated drug in the outpatient setting.

Let me get in the middle of this duel between the 2 of you on this topic because I thought it was interesting. Eunice, I agree with you. As Sasha pointed out, the hazard ratio for survival in the VIALE-A study was not significantly different from 1 for patients azacitidine-venetoclax vs azacitidine-placebo. Here is the issue: It is the sequencing issue, and it is also the response rate because when these patients present, they are sick and need a response. What you could say of both studies is that azacitidine-venetoclax and azacitidine-gilteritinib can control the disease in these patients with 

You are on solid ground choosing either of them. I will let you comment about triplet combinations in a second, but what I will mention what I find interesting here: In Courtney DiNardo’s presentation at EHA [the European Hematology Association 2020 Congress] of azacitidine vs azacitidine-enasidenib, there was no difference in overall survival. And the overall survival in those patients with 

 mutations was remarkable: 22 months, median overall survival. I cannot help but believe that it is because the patients who got azacitidine alone or azacitidine with enasidenib could then receive some other therapy once they relapsed: venetoclax-based therapy or another IDH2 inhibitor. It is the sequencing issue that is going to confound some of these survival studies. I am going to turn it back to you to comment on those things.

Most of what we have learned about giving drugs that target 

 mutations potently—the current second-generation drugs—has been done in the relapsed/refractory setting. That is where we enrich for the leukemia that grows most rapidly and is most 

 driven, and there is no test that can say, “This is 

 driven and this is not” that we have so we can discriminate these. That is where we have seen the benefit of a potent selective FLT3 inhibitor: the relapsed and refractory setting.

To me personally, as much as I want to bring these drugs to the frontline setting to suppress those clones early, we do not know that that is critical. That is why we are doing studies in the frontline intensive setting asking whether a drug like midostaurin or a drug like gilteritinib proves to be the better frontline drug, and we do not know the answer. Midostaurin is a weaker, less selective FLT3 inhibitor, but it may be a better FLT3 inhibitor because it hits all these other targets.

When you get to patients not getting intensive chemotherapy where they see less of the backbone treatment that could suppress the growth of all the clones, what is the best approach? I do not think anybody knows. What we need is a study that randomizes patients between 1 of these 2 approaches, either an HMA [hypomethylating agent]–plus–venetoclax approach—you could even argue an HMA only, like the study that Eunice is describing—vs a combination that includes a FLT3 inhibitor. That LACEWING study is important to define this. It is a randomized trial, and I hope we learn from this what the right answer is. It could be that there is no big difference in part because you are treating patients in the frontline setting. You may select for a growth of leukemia that has nothing to do with FLT3 through that approach.

What the data do show in the frontline setting is that, when patients get venetoclax plus an HMA, they do better than a patient who got an HMA alone in a study that was appropriately powered to answer that question. It was not powered to answer the question of the subgroup of 

 mutations, so I have trouble using a subgroup analysis to say that I should not use what has been proven to be a better drug if I had the option of HMA alone. I personally would have trouble enrolling to a study that had an HMA-only backbone based on the trial results of the VIALE-A study. I have been giving venetoclax plus azacitidine, but I freely admit that I do not know if this is the right thing to do, and we should be doing a randomized controlled trial.

I would agree with the points that you made, Harry, that getting a response is the most important first goal: getting a CR or a CRc. There is no doubt that using venetoclax and azacitidine leads to 67% CR/CRc rate as opposed to 20% to 30% with azacitidine alone. In fact, that is the same rationale that I use to treat patients with 

 mutations with venetoclax-azacitidine. Even though the survival data are not necessarily better, I can get a response, and if I can get a response in those patients, whether they are a patient with FLT3 mutations or 

 mutations, you know what I can do? I can take them to transplant. If I can take them to transplant with little treatment-related mortality going into that transplant, that is the best approach for some of these poor prognostic subtypes of AML.

I have also heard the argument that patients should receive venetoclax-azacitidine, get that into that CR, and do what you mentioned briefly: sequencing. Go ahead and give them venetoclax-azacitidine, and then if they relapse, give them gilteritinib subsequently as a salvage maneuver.

The concern I have somewhat with venetoclax-azacitidine is mostly a theoretical 1. I do not disagree with Sasha, and I would not want to disagree with Sasha, but there are a lot of data coming out from Courtney DiNardo and Andrew Wei showing that 

 mutation is a major mechanism of resistance to venetoclax long term. When they looked at patients and looked at their mutational profiles, having a 

 mutation or the development, acquisition, or selection for a 

 mutation was a primary mechanism by which patients failed venetoclax-azacitidine. This again supports the triplet studies that are being done or at least the 2 double-targeted therapies, which we will talk about in a bit, by Naval Daver and Alexander Perl looking at the venetoclax-gilteritinib combination.

We are lucky to have many options. Whether you want to start with the FLT3 inhibitor azacitidine or you want to start with venetoclax-azacitidine and then switch, there are some data suggesting that venetoclax-azacitidine works best when you use it in the up-front setting. We know that venetoclax-azacitidine in the relapsed/refractory setting can only result in response rates as low as 20% to 30%. For that reason, people also do the venetoclax-azacitidine combination first and save the FLT3 inhibitor. We do not know. Either of these is a great topic for discussion, and we will be trying to sort out these data.

It is the same thing with IDH inhibitors. Are they better? Are they worse? Do they add anything? Is there a survival benefit? We do not know, but I do not think that we have to know. If we can use all these drugs in some sort of combination, and patients can make it 22 to 28 months or make it to a transplant, I do not think people will care how we got to that point.

I agree. My patients want to spend as much time in remission as possible.

 It is about getting in remission and staying in remission on drugs they can tolerate. What we do not know is the combinations vs sequencing and what the best way to do that is.

Management of AML: FLT3 Inhibitors and BCL2 Inhibitors

In this next section, want to focus on targeted therapies. More specifically, we are going to be talking about targeted therapies against 

 mutations, and we will talk a bit about some investigational agents that are getting some of our attention. I want to start with an important topic, and that is the use of FLT3 inhibitors not for patients eligible for intensive chemotherapy. We know from the RATIFY trial, from the German study group, that the addition of midostaurin to intensive chemotherapy improved survival and other outcomes.

Sasha, I want to turn to you about what you do for patients who are unfit for intensive chemotherapy. They are not eligible by age or comorbidities but have a 

 mutation, whether that is an ITD or TKD mutation. How do you choose therapy for those patients?

I can tell you what we do at the University of Pennsylvania Perelman School of Medicine, but despite spending a lot of time studying 

 mutations and trying to be as expert as possible in 

, I do not know that what I am doing is the right thing. One problem we have is that there are a bunch of different options, and we do not know what the proper 1 is. We have good data from the VIALE-A study in patients who are unfit for intensive frontline chemotherapy to say that a combination regimen that includes venetoclax is better than a single-agent regimen with either a hypomethylating agent or low-dose cytarabine, which I do not commonly use as a single agent.

Most typically, I use venetoclax with azacitidine the same way it was used in the 

 paper recently published by Courtney DiNardo and colleagues, which showed a survival benefit for venetoclax plus azacitidine over azacitidine plus placebo. In that study, they did a subgroup analysis of a bunch of different molecular mutations, including 

. They did not break out ITD vs TKD in that study, but they showed that both responses were higher in the combination arm and that survival was better in the combination arm. For the question of what is better, azacitidine vs venetoclax plus azacitidine, venetoclax plus azacitidine beats out azacitidine alone in patients with 

 mutations, with all those caveats. There are no alternatives.

I disagree with that, Sasha. The hazard ratio on that VIALE-A trial was overlapping. For patients with 

 mutations, I am not 100% sure that is correct. I know that Marina Konopleva presented data from her group at The University of Texas MD Anderson Cancer Center at the 2020 ASH [American Society of Hematology] Annual Meeting saying that there was no statistical difference between those who got azacitidine alone vs venetoclax-azacitidine at their institute. I would have to throw that out there.

You are taking the words out of my mouth. I was going to say that, if you look at the point estimate, it was 0.66 for patients with 

 mutations. For the whole study, it was like 0.66 for everybody, which looks the same, but the confidence interval exceeded 1. When you look at that, without the caveats that it is a combination of ITD and TKD, and you break out those mutations, there was no difference in the data that Marina presented for the ITD-positive patients, which raises the question: Should we be adding venetoclax to these patients in the frontline setting? The TKD-positive patients did better, but there was not as clear a benefit there, which brings up a study that you presented in which a FLT3 inhibitor was added to azacitidine: gilteritinib plus azacitidine. That trial is in progress, so we need to see how the trial reads out, but it is at least a feasible approach. You can comment more on the data that you presented, but that is 1 alternative that is about giving a FLT3 inhibitor with a hypomethylating agent.

Role of FLT3 Inhibitors in Chemo-Ineligible AML

Sasha, I know you must have just as many thoughts as Eunice does on this. I am going to go to your expertise, and you can then do whatever you want. Here is my question for you: I gave somebody 7+3 chemotherapy and midostaurin, and I then gave them HiDAC [high-dose cytarabine] and midostaurin and sent off 1 of these fancy MRD [minimum residual disease] assays for the 

 ITD, not the usual PCR [polymerase chain reaction] assay, the 

 ITD MRD assay, and it is completely negative. Does that patient need a transplant still? Should I go with the MRD as the marker or the biology of the disease?

Alexander E. Perl, MD, University of Pennsylvania

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