Welcome to The AML Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Naval Daver, Eunice Wan and Felicitas Thol, who debate key updates in the treatment and management of AML following the 2021 EHA and ASCO meetings.
The topics of discussion include targeted therapies, MRD approaches, maintenance strategies and emerging therapies.
“We saw that patients who had received gilteritinib on the ADMIRAL trial and proceeded on to transplant had some actual long-term survivors with significant numbers of patients surviving two to three years with the combinatorial approach of transplant following gilteritinib.”
– Eunice Wang
“The bottom line of this analysis is, that when you give a standardized protocol and a standardized way of analyzing this protocol, we get very, very similar outcomes. So basically, it is possible to standardize NGS-based MRD and with a standardized protocol, it also appears that the sensitivity of the level is much better than if everyone has its own kind of in-house protocols.”
– Felicitas Thol
Emerging therapies, targets and combinations
“So now we’re switching our approach to other innate immune activating approaches, such as NK cells and macrophages. I think that’s where magrolimab and other CD47s fit in, where they activate not the T-cell immune system, but more the innate immune system and macrophages. Some of the data again, is looking encouraging in the early datasets.”
– Naval Daver
Sequencing and approaches to maintenance
“I think, as you mentioned, there certainly are distinctions between the targeted therapies and conventional chemo. Conventional chemo, typically for intensive, we do a certain number of cycles and we stop. And I think with the targeted therapies, what we’ve seen is, really the most effective approach as long as they maintain that clone is, to continue these drugs for long periods of time. And we’ve seen studies looking at not only combining with upfront therapy, continuing and during consolidation, and importantly now, extending this post-transplant.”
– Eunice Wang
Watch the full session
Naval Daver: Hello. My name is Naval Daver. I am Associate Professor in the Department of Leukemia of the MD Anderson Cancer Center in Houston, Texas. It’s a great pleasure to be here today with my friends and colleagues, Dr. Eunice Wang and Dr. Felicitas Thol. We’re going to be doing a roundup discussion of the ASCO/EHA as well as touching on some of the exciting topics in AML that are coming later this year. With that, I’m going to turn it over to Dr. Wang to introduce herself, please.
Eunice Wang: Hi, My name is Dr. Eunice Wang. I am the Chief of the Leukemia Service here at Roswell Park Comprehensive Cancer Center in Buffalo, New York. I’m delighted to be here to talk about our impressions of the 2021 ASCO/EHA meetings.
Naval Daver: Dr. Thol?
Felicitas Thol: Hi My name is Dr. Felicitas Thol. I’m an attending physician at Hannover Medical School in Germany in Hannover. It’s a pleasure here to join you all. My main interest is AML and MDS. I’m looking forward to this discussion.
Naval Daver: Okay. Well, wonderful. I think, to start with, maybe we can touch on some of the highlights that were presented at ASCO and EHA. Of course, ASCO is a much heavier solid tumor meeting, but I think there were some interesting long-term updates and a few novel concepts. Maybe I’ll turn it first to Dr. Wang to discuss some of the FLT3 updates that she found interesting from both ASCO and EHA and also, how she sees some of these moving into the future.
Eunice Wang: Sure. I’d be happy to. In terms of FLT3 inhibitor therapy, as you know we currently have two commercially approved FLT3 inhibitors, midostaurin, in the upfront setting with chemotherapy as well as gilteritinib as monotherapy in the relapsed/refractory FLT3 mutant AML setting.
Eunice Wang: So, this year at ASCO and EHA 2021, we did see some important updates on gilteritinib as well as its increasing use in combination regimens. There was data presented by Sasha Perl and colleagues of which we participated, looking at long-term outcomes of patients treated on the ADMIRAL trial. In that particular abstract, we saw that patients who had received gilteritinib on the ADMIRAL trial and proceeded on to transplant had some actual long-term survivors with significant numbers of patients surviving two to three years with the combinatorial approach of transplant following gilteritinib.
Eunice Wang: So, this parallel is kind of what we saw in the RATIFY trial where the best survival in FLT3-mutant patients treated with midostaurin 7 + 3 with those that underwent allogeneic stem cell transplantation in CR1, and certainly that is what would be recommended based on this new data in CR2 for these patients.
Eunice Wang: We also saw gilteritinib being used more and more, however, in combination therapy. There is Phase I data presented by Pratz and colleagues with the final results of their Phase Ib study looking at 38 patients with FLT3-mutant disease treated on that study, with gilteritinib in combination with cytarabine and anthracycline-based chemotherapy. This combination was very well tolerated, did not seem to be dependent on anthracycline-chosen, although the number of patients was very small, and importantly, resulted in very high MRD-negative rates as detected by a FLT3 MRD assay performed at successive time points. I believe at the time after second consolidation, 85% of patients were considered FLT3 MRD negative and this has laid the groundwork for a precog study as well as phase three study in Europe comparing gilteritinib 7 + 3 with our standard midostaurin 7 + 3 in the newly diagnosed setting.
Eunice Wang: Lastly, don’t want to leave out my esteemed colleagues at MD Anderson who presented their data as well as with other colleagues on combinations of gilteritinib plus venetoclax and combinations of triplet therapy using a FLT3 inhibitor an HMA, as well as venetoclax for the relapse refractory setting.
Eunice Wang: I’ll turn this back to Dr. Daver to discuss the gilteritinib and venetoclax studies, but just suffice it to say that in the relapse refractory setting, doublets or even potentially triplets, are appearing to be able to be given with some degree of myelosuppression which is manageable, with very high response rates in the relapse refractory setting, even more up to a hundred percent response rates in the newly diagnosed setting.
Naval Daver: Yeah. Thank you very much, Dr. Wang. I think it’s a good problem we have nowadays as to what doublets and triplets do apply and how to optimize them. And absolutely with the venetoclax gilteritinib, which is a multicenter study that we participated in, Jessica Aardman presented the updated data at the EHA meeting. This was in relapse refractory FLT3 and most of these patients, 70% have had one or more prior FLT3 inhibitors. So we know seven, eight years ago we would be expecting a response rate of 10 to 20% with available therapies. And it was very promising to see that in this study, we had an 80% CRC rate, which included count recovery and marrow remissions. Half of these were with count recovery, half of these were marrow remission.
Naval Daver: But as you mentioned, I think the focus, especially in FLT3, maybe IDH NPM1, is moving much more towards molecular annotation of responses rather than just, is this CR, CRI [inaudible 00:05:42]. And what we’re seeing with these combinations is, at least when we compare them to historical single agent gilteritinib-quizartinib data, the molecular clearance rates seem to be much higher at 60, 70% compared to about 20, 30%.
Naval Daver: So, hopefully, these combos will emerge over time to be the next approaches. I think one has to be very careful with myelosuppression. I think especially physicians who may want to try this in the community or in smaller academic centers, I think it would be very important to communicate with one of your local experts who have done this, published it, or have a lot of experience with it because there are a lot of nuances that are not presented as regarding early bone marrow, stopping venetoclax, use of growth factors, dose reductions of gilteritinib, things like that. So I think these are very powerful regimens, but that also means that they can also have severe myelosuppression toxicity if not used appropriately.
Naval Daver: But I do think in the future, doublets or triplets and I don’t know which one will emerge maybe in salvage, the doublet could be enough. Some of the data is suggesting, especially if you want to take them to transplant, maybe frontline, the HMA does have a blanket suppressive effect on other parallel mutations that could emerge. I think this is a learning curve, but I think we do need to highlight that these are quite myelosuppressive and one has to be very cautious and have expertise in using them going forward. But I think overall, interesting future here for targeted therapies.
Naval Daver: With that, let me turn it over to Dr. Thol. So Dr. Thol, there were some updates on the MRD approaches and prospective data now showing use of MRD from the ELN. I think you are very familiar and participated in that. Could you please highlight and update what you thought was interesting there?
Felicitas Thol: Sure, thank you. I think it was really an interesting study with respect to NGS-based MRD, because we all talk about NGS-based MRD, but every group has its own assay and every assay has its own unique level of sensitivity. And the question that the ELN working group for MRD really wanted to answer is, can we standardize it? Can we find a way to standardize it and how can different labs work with the standardized protocol?
Felicitas Thol: So, the study that was led by Michael Heuser and myself was a study where a lot of European groups, as well as U.S. groups participated, and every group got a standardized set of samples and they followed a certain protocol that was given as a standard protocol, as well as their protocol that they use in-house. The bottom line of this analysis is, that when you give a standardized protocol and a standardized way of analyzing this protocol, we get very, very similar outcomes. So basically, it is possible to standardize NGS-based MRD and with a standardized protocol, it also appears that the sensitivity of the level is much better than if everyone has its own kind of in-house protocols. So I think the way to go forward is really to have a standardized program for NGS-based MRD that should also be part of clinical trials so that we all talk about the same thing.
Felicitas Thol: And Naval, I think you already touched an important point. We always look at what are markers doing during targeted therapies. I think one of the challenges will be to follow clonal evolution, like, especially with FLT3 inhibitors. We do know that with midostaurin in the RATIFY trial, 50% of patients lost the FLT3 ITD clone when they relapsed. So we really need to be aware about clonal evolution, we need to look for clonal evolution at the time of relapse and we need to take that also into consideration when we do NGS-based MRD. Because if you just look at one marker, we might be unfortunate and that marker that is being lost is the one that is not driving clone evolution.
Naval Daver: I think that’s a very, very important point. I think we’re seeing this again and again. FLT3 is probably the tip of the iceberg where this is most well-described. A lot of the relapses, especially when we use potent upfront therapies, like induction therapy with FLT3 inhibitors, whether it’s sorafenib that Andrew Wei and the group from Australia showed a very similar phenomenon that many of the relapses after 3 + 7 sorafenib at ASH they had shown this data, almost 50 to 60% were FLT3 negative.
Naval Daver: Similar data, as you mentioned, has been published from the midostaurin subset. So I think it’s quite important that we do sequential NGS monitoring. I think even in the community and other centers, this is probably a message and I think this may not be unique to just FLT3.
Naval Daver: We actually have a dataset coming out with TP53, where we are seeing even emerging TP53 mutations, not as common, but it is seen. Even with IDH, which is historically always considered a founding clone, we definitely have seen a few patients. Now, it could be a sensitivity issue. That’s always the question, is this true emergent or is this expansion of a very small clone that our traditional commercial NGS will not capture? That we don’t know, but I think the point is, now that we have all these therapies, FLT3 inhibitors, IDH1 and 2, maybe hopefully menin inhibitors that target MLL and NPM1, maybe drugs like magrolimab and APR that target TP53, it’s going to be critical to look for these because I think that will give our patient the best chance if we can find a targetable mutation and use that particular therapy.
Naval Daver: So, I think that this is a great effort by the ELN and not only in using MRD for prognosis after therapy, but also to understand what forms of relapse and how different molecular relapses could occur. Any comments on that, Eunice?
Eunice Wang: Yeah, so I do think that that’s very important. Clonal evolution is just yet another challenge that we have for the treatment of AML. I think in the context of that, I think it’s interesting to discuss the IDH inhibitor data combining IDH inhibitor IDH1, plus azacitidine and axitinib plus azacitidine for treatment of IDH1 and IDH2 mutant disease. As you know, this was a trial where IDH1, IDH2 mutant-disease sponsored by Agios were randomized to receive either the IDH inhibitor plus azacitidine versus azacitidine alone and looking at event free survival, overall response, as well as biomarkers including for axitinib 2HD and the variant allele frequency.
Eunice Wang: So, somewhat disappointingly, although there was significant improvements in overall survival, 60, 70% as opposed to 20 or 30% with azacitidine alone, and there was some improvement in event-free survival, overall survival was not significantly enhanced by using the combination of azacitidine plus the IDH inhibitor. That was very surprising because given the differences, and there were also marked differences in the biomarkers and the amount 2HD suppression that you were getting with inclusion of an IDH inhibitor and suppression or decreases in the variant allele frequency. So why didn’t this translate into an overall survival advantage?
Eunice Wang: So, it is hypothesized that potentially many of the patients who had received azacitidine alone in the control arm went on to get sequential therapy with an IDH inhibitor and so that may have been the difference in not having any significant gap between the two treatment arms. I don’t think that we should necessarily view those as negative trials, but just as an important reminders that there is the biomarkers and there’s the molecular studies and there’s also the reality and what happens in the clinic.
Eunice Wang: This study would sort of argue against using these molecular or biomarker studies, and I would say, no, I think I would be more comfortable moving forward with, if I was to give IDH inhibitor and combining it with HMA therapy, particularly because as was mentioned by my colleagues, there is that potential for clonal evolution. So having the HMA on board with the targeted therapy offers a backbone that could, over the longterm, although it hasn’t been demonstrated, suppress the development of additional clonality, but those studies I think, are going to be debated, I think for a little while. So I thought that data was very interesting.
Naval Daver: Yeah, I totally agree. And as of course, you’re very familiar, the similar data has been, at least press-released from the AZA-gilteritinib versus azacitidine, the LACEWING study, that we cannot discuss any details, but we do know that the AZA-gilteritinib did not improve the primary endpoint, which is overall survival on the interim analysis. And I think this is kind of getting into a broader question and it probably will require, and hopefully sooner than later, readjustment of how we conduct these trials and what endpoints we look at, because I think 10 years ago, when all we were using was traditional intensive chemo, 3 + 7 CLAG-based regimens, MRD negativity by flow or achievement of CR really did correlate very well with survival.
Naval Daver: But I think in the era of these targeted therapies, and I think this is going to get even much more complicated in the era of immune therapies, hearing what we do from all our solid tumor and lymphoma colleagues, I don’t think that those may be the ideal surrogates anymore for response. So I think as we use these agents looking at things like time to next therapy, duration of remissions, molecular clearance are probably going to be more important than just pure, is it a full CR versus not?
Naval Daver: I think that has to be done because when you look at some of these data, for example, with the AZA IDH versus AZA, you clearly see that the true CR rate was 55 versus 12%. Of course those patients who are transfusion independent and so there’s a huge quality of life improvement. Even though at the end of the day, they may have lived 24 months, how do they live those 24 months? Was it much less time in the hospital, much less transfusions, better count recovery, quality of life? This is stuff that I think other groups that started to collect in AML maybe important going into the future. So very, very important to start looking at the trial designs and endpoints coming forward.
Naval Daver: What about other therapies emerging? Some may have been discussed, may not have been discussed at EHA/ASCO. Dr. Thol, what is of interest right now in Europe in the immunotherapy, new targeted therapy arena?
Felicitas Thol: Yeah. So maybe of note, ivosidenib and enasidenib did not get approval by the EMA. So for us, these agents are not available. We took part in the clinical trial so we do have experience with both substances. I was also surprised by the trial results, that the combination didn’t really lead to an improved overall survival. Disappointing, that’s really disappointing but as you already mentioned, it’s really also the question, what are the important outcomes. I think we have to ask ourselves, what are clinical meaningful outcomes and what are the FDA and the EMA looking at? Because for us in Europe, it’s important that the drugs get EMA approval. If you don’t get EMA approval then we cannot use the substances. Therefore, I think it will be important to really see what is meaningful for the patient and then convince the authorities and the FDA and EMA of that.
Felicitas Thol: For us in Europe, I think it’s a similar development as in the United States. Magrolimab is an interesting agent. We are all kind of hoping for immunotherapy, especially BiTEs or CAR T-cells, but as we do know here, we are really not very advanced. I mean, the CAR T-cell program is really disappointing as compared to the ALL CAR T-cell program. We do have some targets like CD33, CD123 and also FLT3, which I think is interesting, but so far, I think we really see challenges. And the challenges in AML are related to not all AML cells expressing the target, like the target of 123 or the target CD33 or FLT3, and also the problem, if it’s expressed, it’s not just expressed on AML cells, it might also be expressed on normal hematopoiesis, and this of course can lead to horrendous hematotoxicity. So I think there will be still some challenges to overcome before we have good CAR T-cells for AML.
Felicitas Thol: But I think we are dreaming of that and I think in the meantime, it will really be combination therapy. As you already mentioned, that we combine venetoclax with HMA and other agents. And for us in the AMLSG, in the AML study group here in Germany, we cooperate with the Hovon study group. And I think we have some interesting trials coming up looking at combinations like ivosidenib, enasidenib with intensive chemotherapy. And if you think about it, it’s amazing how many patients you need to screen in order to fill the trial. So it’s a huge trial and it’s a lot of screening that needs to be done, over 800 patients are supposed to be included, but just think about how many patients need to be screened with a frequency of IDH1 and IDH2 mutations. So that trial is ongoing.
Felicitas Thol: Another trial, which I think is also interesting in frontline therapy, 7+3 plus midostaurin versus gilteritinib because right now I’m using gilteritinib only in the relapsed/refractory setting and I think it will be interesting to see what role it has in the frontline setting in combination with intensive chemotherapy. But then I think the big thing will be for the non-intensively treatable patients, the combinations that we already discussed, triplets.
Naval Daver: Great. Yeah. Eunice, any thoughts on upcoming stuff?
Eunice Wang: I just wanted to focus on sort of a new targetable subgroup. So NPM1-mutant patients constitute up to 25 to 30% of our newly diagnosed patient population. We know that that tends to be as you mentioned with IDH, a founder mutation, but up until now, we’ve had difficulty in really using NPM on mutations, other than knowing that there are favorable prognosis to determine really outcomes or targeted therapy for those patients.
Eunice Wang: I think moving into the future, there was a couple of new developments, which I’m sort of excited about for that subset of patients. One is, the data updated analysis from the oral azacitidine QUAZAR Phase III study, which presented by Dr. Döhner and colleagues which demonstrated subgroup analysis of patients who had benefited in the QUAZAR study from the addition or the use of oral azacitidine following induction consolidation chemotherapy for those individuals who were in morphological CR, but unable to proceed to allogeneic stem cell transplantation.
Eunice Wang: Now, a couple of caveats with that trial. Most of the patients on that trial did not receive three to four cycles of consolidation chemotherapy. The overwhelming majority of them received one or at best two. So we don’t know potentially, based on that patient selection, what patients who had gotten the full four cycles of IDAC would have done. But clearly when they did the subgroup analysis, patients who are NPM1-mutant had vastly superior overall survival over patients who weren’t NPM1-mutant, who had received placebo only. That may just be because NPM1 is a favorable marker for patients getting cytarabine-based therapy, but the differences between the two groups were obtained, which were pretty striking. So, it begs the question of, for those patients who had NPM1 positive, whether that would be a marker that we would be potentially pursuing oral azacitidine after even two or three or four cycles of IDAC. I don’t think the QUAZAR study addresses that, but certainly it’s making us look up and say, “If you are NPM-mutant, are we going to treat those fit intensively, treated patients a little bit differently than we do now?” new standard of care type of discussion.
Eunice Wang: The other interesting development which has been presented over the last few conferences is really, as you mentioned, the use of menin inhibitors targeting the menin epigenetic complex, which regulates transcription in patients who are NPM1 as well and KMT2A rearranged. So no real data updates at this meeting, but certainly there are two menin inhibitors in phase one development for both NPM1 mutant and KMT2A rearranged, one from Kura Oncology, the other from Syndax. Early Phase I study seems to suggest that patients with those target mutations can have responses to both of those inhibitors, that they’re fairly well tolerated with maybe some QTC prolongation interaction with azoles. So, I am increasingly enthusiastic about the possibility that we may now be having newer therapies for those patients with NPM1 and other mutations.
Naval Daver: Yeah. Thank you. I think that there’s a lot of exciting drugs coming along, absolutely. As many of them mentioned by Felicitas and Eunice. I think for TP53, we’re quite excited about this group of CD47 and SIRP alpha that was mentioned in one of those that’s most advanced is magrolimab, but there are many, many others that are also now into clinic with ALX and Trillium and others.
Naval Daver: I think this will be both conceptually and clinically very, very important and nice to see it progress because for many years we’ve been working on different immunotherapy approaches and we tried the traditional immune checkpoints using T-cells such as PD1, PD-L1, CTLA-4 for many years, hoping that like solid tumors, lymphomas, there could be benefit in AML and MDS. Unfortunately, after trying many different combinations and approaches, these drugs don’t seem to have the same degree of benefit. Part of this may be related to T-cell dysfunction. A lot of papers are now coming out as to fitness of T-cells and T-cell infiltration and how this is really abrogated in myeloid malignancies.
Naval Daver: So now we’re switching our approach to other innate immune activating approaches, such as NK cells and macrophages. I think that’s where magrolimab and other CD47s fit in, where they activate not the T-cell immune system, but more the innate immune system and macrophages. Some of the data again, is looking encouraging in the early datasets. Of course, we need mature data and two randomized phase threes have started, one in MDS frontline of AZA-magro versus AZA and then one in AML, especially in that very difficult unmet need TP53 of AZA-venetoclax versus AZA-magrolimab. So we will see, and hopefully one or both of these will bring this new class of immunotherapies.
Naval Daver: The other, I agree. I think CAR-Ts eventually will find a place in AML, but I think we’re a few years away. The challenges we have as you mentioned, Felicitas, compared to ALL are one is, we don’t have as specific and as well-marketed markers. For example, CD123 is expressed on the endothelium, is expressed in pulmonary tissue, cardiac tissue, CD33 of course, in the liver. So the problem is, if you have a very high potent target towards a agent that targets these markers, you also start getting a lot of toxicities in these organs, unlike for example, CD19, which is almost exclusively on the surface of the B lymphoblasts and you can really attack it very aggressively. So, maybe dual CAR approaches, or maybe using CARs with suicides switches, or having early transplant as a bridge if you achieve MRD negativity, I think we will have to be a little bit more innovative in AML.
Naval Daver: Then recently I was quite interested to see some, it wasn’t presented at ASCO, but there was a press release using NK-cell therapy in AML. There’s a group called [inaudible] with FD156 being their lead compound. This is not a CAR, it’s actually just high volume CD16 activated NK-cells that are being infused. They released that they had 5 out of 12 CR/CRis in multiply relapsed AML. They actually showed data in lymphoma, which looked quite fantastic, 9 out of 11 CRs in multiply-relapse lymphoma using the same approach. So the question now is, do you really need a CAR, or could you use high volume NK-cells, do ADCC, target leukemia cells and potentially get higher responses without any of the CRS or ICANS or infusion reactions?
Naval Daver: So, I think there’s a lot to come in both immunotherapy and targeted. I completely agree with Eunice. I think the menin inhibitors, even though the data is very early, are clearly the demarcating themselves as very, very active drugs, high potency, single-agent activity, even in fourth and fifth salvage. Overall, well-tolerated, many of them, the first two Syndax and Kura are in-clinic, others have started early clinical trials, Daiichi, J&J and others. So the data looks like these could be like IDH FLT3, or maybe even more potent based on the 50 to 60% responses that are seen. And of course, again, quickly moving them into combinations, frontline, maybe adding them to HMA and all of these approaches could be of interest. So I think a lot that will be coming going forward with these different drugs and approaches.
Naval Daver: Any other interesting thoughts, or presentations? I know Eunice, you mentioned that there was some long-term updated data with gilteritinib. What were your impressions of that overall and how does it impact your practice if any?
Eunice Wang: Well, I think it’s important when using some of these targeted therapies to continue to use these targeted therapies. I think, as you mentioned, there certainly are distinctions between the targeted therapies and conventional chemo. Conventional chemo, typically for intensive, we do a certain number of cycles and we stop. And I think with the targeted therapies, what we’ve seen is, really the most effective approach as long as they maintain that clone is, to continue these drugs for long periods of time.
Eunice Wang: And we’ve seen studies looking at not only combining with upfront therapy, continuing and during consolidation, and importantly now, extending this post-transplant. I think that in these patients treated with gilteritinib long-term on the ADMIRAL study, almost invariably, all these, and most of the majority of those patients went to transplant, but the common denominator is that they all stayed on their gilteritinib.
Eunice Wang: I have a patient who is a long-term survivor, who post-transplant he was on her third year of gilteritinib maintenance with no evidence of disease. So I think that, that is the importance of saying some of these targeted therapies, they need to be continued indefinitely to have the most efficacy.
Eunice Wang: I think that one of the things that is less exciting but is looking at changing our backbone therapy for some of these targeted therapies. We’ve seen the emergence of oral hypomethylating agents as probably the most practical and requested agents in my clinic from both patients and community providers is, when can I start using oral azacitidine, or oral decitabine in place of parenteral HMA therapy for patients with MDS and AML at every stage. I think we are getting there, obviously the oral azacitidine is different pharmacokinetically from systemic azacitidine. So for those people who are thinking about this, please do not use oral azacitidine the same way that you would use IV or subcut azacitidine. It’s a completely different formulation, different pharmacokinetics. It’s not the same drug.
Eunice Wang: There are studies that are looking at some of those in those settings, but clearly not a one-to-one substitution. In contrast, the oral decitabine compound is been shown in detailed pharmacokinetic analysis to be very equivalent one-to-one with the systemic or the IV decitabine. So for that drug, we use it for five days, similarly to our five days of decitabine. However, in the U.S. at least, the oral decitabine complex is not indicated for newly diagnosed AML. It’s only indicated for high-risk MDS. So, there are a number of ongoing trials using one or both of these agents.
Eunice Wang: As a new backbone, we have a trial looking at the oral decitabine replacing azacitidine in combination with venetoclax. There’s a number of maintenance studies. So that is on the horizon, but I think right now that we’re not using those off-label just because of the potential risks, and definitely we’re not using oral azacitidine as a substitute.
Eunice Wang: We also saw data presented by Jessica Altman again at the ASCO meeting, but a novel sort of more potent new cytarabine ASP… ASP… I don’t remember the name of it, a new cytarabine formulation which was studied as a single agent in unfit AML patients and had very encouraging tolerability safety profile and high response rates about 30, 40% was well tolerated. Single therapy, again, may not represent the current standard of care, but gives us some potential about whether this novel cytarabine could be a new backbone theoretically in combination with venetoclax or in some of the more upfront regiments FLAG or CLAG or something like that, that we could be using a combination with or without targeted therapy.
Eunice Wang: Now, the only caveat with that being was that the, again, another quote unquote, negative study was venetoclax plus low-dose cytarabine, the VIALE-C trial. There was no overall survival benefit in that despite higher CR rates, overall response rates. So it’s not clear whether practitioners, at least in the United States, would be using another cytarabine backbone in combination with venetoclax as opposed to our colleagues in Europe, who would potentially be more familiar with that. I would say that most of us here would still favor an HMA backbone in combination with venetoclax, but I think that the drug does have some potential, some legs moving forward.
Naval Daver: Yeah, I think the oral HMA is a very important point. I think this is going to change practice over years. I don’t think we’re there yet. I mean, it’s not a superiority argument like the menin FLT3 and IDH, but I think it is a major convenience factor. Also, conceptually, to be able to give oral or a doublet, let’s say, or oral or a triplet even if we get there in the next couple of years is going to be quite amazing given that 10 years ago, we were pushing high dose intensive chemo for everybody with very limited other options.
Naval Daver: But I think it is important to caution that we don’t yet have any data combining either the oral decitabine [inaudible] or the CC486 oral azacitidine with venetoclax. Those studies are ongoing. Hopefully, they will show equivalence, especially I agree with Eunice the oral decitabine, I think is the one that we’re most comfortable with for equivalent, given that it was approved based on bio-equivalence whereas oral azacitidine was approved in a specific setting maintenance where in fact, the fact that it delivered only 30 to 40% of the true total IV azacitidine may have been the big benefit that you’re giving a chronic lower dose over time, rather than a full dose. So will that translate then if you use CC486 plus VEN frontline? We don’t know, we just have to wait for those datasets to emerge.
Naval Daver: But let me turn this to Felicitas. So in Europe, how is the maintenance being viewed? Do you think this is something that will catch on big time or not yet?
Felicitas Thol: Well, I think we do have now good data for the CC486 and it has also recently been approved in Europe, so a little bit later than in the United States, but it’s now available. I think it’s an interesting drug. We took part in the trial ourselves. I think the big decision now will be, if you have a patient at the age of 65 who has some comorbidities, do you treat them with, or him with intensive chemotherapy followed by maintenance CC486 or do you choose AZA-VEN upfront?
Felicitas Thol: We don’t have a direct comparison for that right now. I think that will be a good question in the future because obviously the benefit at the beginning for the patient starting with AZA-VEN is that you can do it as an outpatient. You don’t need to be an inpatient and whereas if you start with intensive chemotherapy upfront, you’re not allowed to forget that, especially in patients above the age of 60, there’s still early mortality, which you may fear, and patients going into the trial in the CC486 trial, they were already in remission. So, the trial started with a patient population that already survived the intensive chemotherapy. So it will be interesting to see in the real world how these two options play out and who will go for what. Yeah, we’ll have to see.
Felicitas Thol: Otherwise, for maintenance therapy, I think it will be really important to address the issue of how long do you need to keep the patient on the FLT3 inhibitor. I think Eunice pointed out very nicely that it’s still important to transplant the patient who is on gilteritinib. Long-term cure is best achieved with allo-transplant and possibly gilteritinib after allo-transplant. I think the SORMAIN trial, which I think was presented at ASH two years ago, pointed out quite nicely that post-allo, TKI have a very important effect in FLT3 ITD-mutated patients and that patients who are treated with sorafenib versus patients not treated with a TKI do better with the sorafenib. But what you can also see is, once you stop the TKI, relapse occur again. So I think we are still not sure how long do you need to treat the patient after stem cell transplantation with a TKI.
Naval Daver: I think that that’s a great point and I think post-transplant, at least in our group, we absolutely are using maintenance in the FLT3-mutated patients where gilteritinib is kind of what we’re using on an ongoing study. sorafenib, as you said, the SORMAIN and the Chinese, a large steady hundreds of patients on each arm, both published one in JC or Lancet Oncology showed a clear RFS and OS benefit. So I do think using maintenance post-transplant FLT3 inhibitors is really now quote unquote, standard of care approach. Of course, there’s the largest of those studies, which is the BMT transplant network study of gilteritinib versus placebo. 400 patients, post-transplant, randomized to the FLT3 inhibitor versus observation that hopefully will read out in the next six to eight months. If that shows clear benefits, then I think we’ll put gilteritinib in a clear approval path for post-transplant maintenance with FLT3 inhibition. So that I think would be very, very interesting going forward.
Naval Daver: And I agree. I think one of the closing thoughts is, I think we’re going to have a competing challenge, but again, it’s great to have this issue compared to 10 years ago of AZA-VEN or AZA-VEN triplets versus induction maintenance, right? Because now both of them are showing improvement, but I completely agree with you Felicitas that as in our group and for me personally, and I’m sure Eunice has the same issue is, how do I find that 50 to 70 year-old patient, who I felt was unfit enough to not get to transplant-
Felicitas Thol: Exactly.
Naval Daver: … but I didn’t feel unfit enough that I gave him induction. So you’re right. If I already feel that that patient has comorbidities, cardiac, pulmonary issues, PS is poor, I’m usually going for HMA-VEN, or now maybe even HMA-VENwith an IDH, HMA-FLT3, HMA-VEN whatever, magro, all of these combos, versus if I give intensive, then sure, there’s a few people who fall apart with intensive chemo, 5, 10% and cannot make your transplant. But for the broad majority, yeah, I’m pushing towards transplant.
Naval Daver: So, I think the next really critical trial will be, if you give induction, you get a remission, then you do maintenance versus transplant, could maintenance then in some way, equate or replace transplant. But without that, we have had a big challenge. I mean, I really have not been able to find patients to start CC486. Eunice, what’s your experience there?
Eunice Wang: I do think that CC486 is an advantage for the, again, those select patients, 50 to 75 who get intensive, but can’t go on to transplant. But I must point out that some people would argue whether the oral azacitidine really represents a true maintenance drug. Because a true maintenance drug in mind is something that is like the ALL maintenance. So you take it for two to three years and the disease never comes back.
Eunice Wang: If you look at the data with the oral azacitidine in a QUAZAR study, one could argue that it just delays the time which people leave. And if you take the terms out for enough, they conjoin. So the data with this trial looks a lot like the AZA 001 trial, where you gave azacitidine to patients who had MDS and you delayed the time until they develop leukemic transformation and die, but everybody just died. So one could argue that the oral azacitidine also, everybody dies. They just, and the curves do… at the beginning, they’re separate and then they come together. So this is not truly maintaining the remission and curing people, just delaying it. So I would argue that for these patients who are fit enough for an intensive chemotherapy, as Dr. Thol mentioned, the optimal is to go for a allogeneic stem cell transplantation.
Eunice Wang: The other question that gets asked a lot is, can I give CC486 or oral azacitidine after VEN-AZA induction, right? So instead of an intensive induction, giving them a less intensive induction as we move more and more towards that potentially being an option, particularly for some patients. Is that going to be used in that setting? There’s no data in that setting for the use of CC486, but that’s the challenge that we get is, as we’re getting more people into achieving a response in the unfit category, what are we doing? Are we continuing both drugs? Do we drop one? Could we substitute an oral HMA instead?
Eunice Wang: I think there’s a lot of questions and I know we’re wrapping up, but I think one of the challenges that we’re getting now is, who is the best patient for VEN-AZA induction? Should it be a younger fit patient with poor karyotype? What if the patient has p53 disease? Should we not be doing VEN-AZA? If they have a low variant allele frequency, should we actually be doing cytarabine-based therapy and send them to transplant? Because we know that p53 patients treated with VEN-AZA don’t do well.
Eunice Wang: What about the FLT3 mutant patients? We know they can recur after VEN-AZA. Maybe we shouldn’t be giving VEN-AZA to those patients, but with the so far presented-negatively SWING study, should be giving a TKI in that population? So as our standards have changed and we have more options, I think that we’re now sort of questioning what is going to be our backbone. I do agree for the younger fit patient, allotransplant still provides, despite all of these targeted therapies and novel things, really still provides the best curative therapy.
Naval Daver: Yep. And I think we don’t have to feel bad about that because look in myeloma, they have 15 drugs and the best triplet and quadruple-
Eunice Wang: Still, we don’t want to be inferior to myeloma.
Naval Daver: Yeah, and they continue to use allotransplant, which is still, I mean, it’s a total therapy, as long as you can get that median survival up to 14, 15 years for a 60 plus patient. I think whatever we do to get there for today is sufficient.
Naval Daver: But I think with that, we’ll wrap it up. It was a great discussion of just not EHA/ASCO, but also the global scope of AML and where things are heading. I think in the end of the day, if you look at some of the recordings from 10 years ago, this is fantastic. I mean, we would be talking about doses of anthracyclines and 60 versus 90 versus 45. It’s great now to be talking about the doublets and the triplets of targeted therapies and maintenance and new approaches. So a lot of progress and thank you so much Dr. Thol and Dr. Wang for joining us and look forward to seeing you all soon.