A session with experts Naval Daver, David Sallman, Eunice Wang & Amir Fathi, who discuss the latest updates in acute myeloid leukemia (AML) following the 2020 ASH Annual Meeting.

Welcome to The AML Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Naval Daver, David Sallman, Eunice Wang & Amir Fathi, who debate key updates in the treatment and management of AML following the ASH 2020 virtual Annual Meeting.

The topics of discussion include venetoclax-based regimens, bispecific antibodies, FLT3 inhibitors and menin inhibitors.

Venetoclax-based regimens

“So I think as we move into venetoclax and azacitidine based on VIALE-A being our new standard of care, the temptation is for many people, including our group, is to just use it as agnostic of mutations in any older, unfit individual coming through the doors. . . . And I think that that may be true for people in the community. There certainly is validity certainly, but as we do more subset analysis, as David pointed out, there are some groups that don’t do as well. So I think mutational profiling still may be indicated. Now, there’s a lot of debates even amongst ourselves.”

– Eunice Wang

Immunotherapy

“I think what’s nice at least with magrolimab is we do get on-target anemia which can be a major issue in cycle one, and we need to keep these patients at a higher transfusion goal during that month for safety. But we don’t really see a worsening neutropenia or thrombocytopenia toxicity and thus may combine quite nicely as a triplet-based regimen given we have sort of a new standard of care with HMA-ven.”

– David Sallman

“There are just so many drugs. There’s so many trials and there’s so many combos. So are we still going to have these large randomized Phase III’s going on for years, or are we moving more to solid tumor or myeloma approaches where you get signals, PFS, OS?”

– Naval Daver

Bispecific antibodies

 

“This is partly because of the regulatory landscape and what was allowed and not allowed, we’re not using them where we should use them, right? We have 10 years now, plenty of experience, where we know the best activity is in that low burden, MRD, early salvage, fit T-cell population, and we really never have been able to try any of those five BiTes in that setting. Now finally I think some of them are moving there, and I think that will be the real proof whether it works or not.”

– Naval Daver

FLT3 inhibitors

 

“Nowadays when you give gilt and ven and all these drugs that have potential for myelosuppression, you do get a CRI, but what is that CRI? What’s the nature of that CRI? And I think that’s an important consideration because, you know, having a totally MRD negative CRI is very different than having a CRI after 7+3 for complex carrier type AML or MDS AML.”

– Amir Fathi

Menin inhibitors

 

“KO-539 is an oral menin inhibitor and inhibits the interaction of menin with the MLL rearranged epigenome complex which is a key component of the pathogenesis of MLL, rearranged AMLs, as well as MPM mutant acute leukemias. Early data with this once daily oral inhibitor suggests that it’s very well tolerated at doses up to 400 mg.”

– Eunice Wang

Full Transcript

Naval Daver:
Hello, my name is Naval Daver. I’m in faculty in the Department of Leukemia at the MD Anderson Cancer Center. Today I have the pleasure of having with me Dr. Eunice Wang from the Roswell Park Cancer Center, Dr. David Sallman from Moffitt Cancer Center, and Dr. Amir Fathi from MGH (Mass General Hospital). Today we’re going to be talking about updates in acute myeloid leukemia from the recent ASH 2020 meeting. There was a lot of new data, a lot of updates, subset analyses, as well as new, exciting drugs. So with that, I think I will just proceed into the discussion.

Naval Daver:
So as we’ve seen in the past, venetoclax continues to be a major drug in acute myeloid leukemia. New updates at this year’s ASH on that. Maybe we can start with some of those. So Amir, what were some of the venetoclax updates that you found interesting? Either novel combos or new therapeutic approaches?

Amir Fathi:
So, venetoclax was presented from multiple different angles. Pretty much it seems like it’s a tradition now these days to talk about venetoclax because it’s so effective in combination. I think you and I had previously talked about the combination of CPX-351 and venetoclax, presented by your colleague, Dr. Kadia. I thought the data was intriguing, very high response rates. But, you know, as the presenters acknowledged, when you sort of combine Ven with a highly marrow-suppressive regimen, it can be challenging. So there was lots of dose reductions, lots of changes to the schedule of venetoclax that was presented. Ultimately, I think they found a schedule and duration that seems to work for venetoclax and CPX-351 of shorter duration, and it seems that it’s feasible. Now, whether this is a regimen that ultimately will incorporate itself into conventional care, I don’t know. I think time will tell. We will have to see. There are other regimens out there.

Amir Fathi:
There is also the combination of FLAG-IDA and venetoclax that again has been predominantly studied by your group both in the upfront and the relapsed/refractory setting. That to me seems very promising, very high response rates, predominantly in the newly diagnosed setting, but also in the relapsed/refractory setting. It seems that it was a bit easier to sort of figure out, or perhaps it was a bit more proactive in terms of figuring out the dosing of venetoclax with that regimen, or it may just be that FLAG is less marrow suppressive than CPX-351 is, but I was also impressed by that data.

Amir Fathi:
Finally, or in addition to that, there was a few updates regarding VIALE-A, and perhaps others are going to talk about that, but I was particularly overall impressed by the data regarding dose reduction of venetoclax sooner than previously recommended and disseminated so that patients can tolerate this regimen from cycle two going forward, as they ultimately achieve response and remission. So those were my takeaways.

Naval Daver:
Yeah, thanks, Amir. A very broad topic, obviously, but yeah, I think the FLAG-IDA/venetoclax that we’ve been doing is I think, maturing well. We had to adjust the doses as you said, decrease the cytarabine from 2 to 1.5, decrease the IDA from 8 to 6, and the venetoclax is 14 days. But in that regimen at least in the last year in early salvage as well as in front line, it seems very safe, but also high remission rate. So I think that’ll be one definitely to look out for. In fact, in salvage 1 and 2 where the median survival now is between 14 and 18 months with about 40 patients, if that continues, definitely something to take forward. But speaking about the subsets, I think that’s a great topic. So, maybe I’ll ask David to talk about some of the data with aza/ven and TP53 AML. He may have seen some of that data. What is your feeling, David, since you’re doing other TP53 drugs? Is aza/ven something you would still consider, or you think it’s out of the question? What are your thoughts?

David Sallman:
Sure, so I think really from the early aza/ven experiences, we knew that TP53 was a challenge from DiNardo’s earlier publication, you know, median overall survival was 7.2 months despite a higher response rate. And that’s really very similar to what single agent hypomethylating agent has been. I think that’s been now seen in multiple studies. I think the VIALE trial, we know that the hazard ratio across this one, although we don’t really have the specific median OS and the P53 subset from that cohort, we know that again response rates are higher but likely from lack of durability and quality of response. These patients are still doing poorly. I think what was nicely shown by your group too, you know with an extended schedule of decitabine up to 10 days and venetoclax, no matter how you slice it, if anything now things are getting worse. Like median overall survival across groups was now between 4 and 5 months, which may be even a little bit shorter, and it may have to deal with the degree of myelosuppression that these patients have with sort of lack of response.

David Sallman:
So I think together, I mean, response rates are higher. It’s not that off study I wouldn’t consider it, but I really think that we can clearly change the standard of care. And so instead of necessarily joining HMA venetoclax, I think some of the studies are looking to be against HMA venetoclax. So we presented data on magrolimab, of course, as you know, with azacitidine and actually have dosed 47 patients, which is large, or as large as any P53 cohort. Our response rates are about in three-fourths of patients with nearly half having complete remission. But I think, again, responses are not the key, and although follow-up is still somewhat short, our median follow-up was five months. You know, our median OS with that combination is now nearly 13 months, and I think that could actually extend farther with many patients still on treatment.

David Sallman:
So that’s really supporting a Phase III to be launched of aza/magrolimab versus aza/venetoclax, but I think there are other strategies, some agents not necessarily discussed as much at ASH such as eprenetapopt, you know, we’re looking at that. And then whether or not triplet combinations can, based on pre-clinical translational studies, can there be synergy with venetoclax. I think that’s a separate question, but I think HMA-ven, to your question, is not a great standard and we can look to improve that even with other doublets, but open to what others think about this molecular subset as well.

Naval Daver:
I like how you said eprenetapopt. I still cannot say that. I’m going to stick with APR for that. And Eunice, you’ve also treated a lot of people with venetoclax, so there was also data in FLT3 mutated AML. The way the data was presented, as Marina was here, we could’ve spoken to her about that, she presented the data, was that yes, the response rates are high and aza/ven is a good regimen to use. However, you know, we’ve discussed this in other forums, that would you really do aza/ven in a newly diagnosed FLT3 ITD AML, and I want to get your thoughts on that data and what your approaches are for a newly diagnosed FLT3.

Eunice Wang:
So I think as we move into venetoclax and azacitidine based on VIALE-A being our new standard of care, the temptation is for many people, including our group, is to just use it as agnostic of mutations in any older, unfit individual coming through the doors. So, if you are 75 or older, or you look unfit, why not just give you venetoclax azacitidine. Why even bother waiting for the mutational profile to come back in 3 to 5, or 7 days? And I think that that may be true for people in the community. There certainly is validity certainly, but as we do more subset analysis, as David pointed out, there are some groups that don’t do as well. So I think mutational profiling still may be indicated. Now, there’s a lot of debates even amongst ourselves. We can have this conversation about whether venetoclax azacitidine represents a reasonable approach for patients with FLT3 mutant disease, or should we reach into our toolbox and get a FLT3 inhibitor?

Eunice Wang:
So, Marina, on a playlist poster demonstrated that patients with FLT3 TKD did very, very well with venetoclax azacitidine, and that should probably be an option valid use for them. However, FLT3 ITD both in the VIALE-A and in the retrospective data from MD Anderson suggests that there is a high response rate, but the overall survival is not quite there. So some people are very convinced you get an adequate response rate, you get several months of response, you get 10, 12, 14 months. But when you look at the hazard ratios, they’re not as clear-cut, and with the availability of things like gilteritinib and other potent second generational FLT3 inhibitors moving into the clinic, I think there’s a lot of question. We also know again based on data done in Dr. Konopleva’s lab that a major mechanism of resistance to venetoclax-based therapy is FLT3, so FLT3 is either selected or closed out or is a clone that contributes to refractory disease, and if you have refractory or relapsed disease to ven/aza, your overall survival is a matter of months.

Eunice Wang:
So I presented some data at this meeting looking at a Phase III trial of gilteritinib plus azacitidine in older, unfit, newly diagnosed AML patients. That data is encouraging. About two-thirds of patients out of a very small group of 15 patients treated on a safety cohort with gilteritinib 80 to 120 mg demonstrated a response, and for at least one patient, that clinical response lasted over 36 months. Median overall survival out of those 10 of 15 patients achieving a response on gilteritinib azacitidine was over 10 months, which is reasonable, and within the range that we would obtain with ven/aza. So the results of the larger randomized Phase II or Phase III cohorts involving almost 200 patients is still pending. That trial is about over half accrued, so over 150 patients enrolled. So we’re going to have to see, but the question remains, as you said, should we do FLT3 inhibitor plus aza? Should we do venetoclax plus aza? Or, your favorite, your proposal is always to think about triplets. We don’t have the triplet data yet, but we do have the doublet data of ven and gilteritinib in the relapsed/refractory setting. That seems to be highly effective with overall response rate of 80% or more in patients that have failed prior ven/aza or who have failed prior gilt.

Eunice Wang:
So I thought that data that you presented was actually very intriguing, and I know a lot of us are reaching, maybe off label, for the combination of gilt and ven. Although having to keep in mind what Amir said, any ven combination is associated with myelosuppression, and I think that was an issue that you have, and maybe you can talk to us more about that.

Naval Daver:
Yeah, absolutely. I think with ven it’s too much of a good thing situation, right? Where we always like to use it and we’ve used it quite a bit, and I think the problem is that in most regimens we’re seeing that not, forget about 28 days, I think ship has already sailed, but even 21 days of ven in these novel combinations is too much. And when the responses are this high, really, do we need that much? And I think it’s always this fear of FLT3 is an aggressive disease, or relapsed AML is an aggressive disease, so nobody really wants to start with 7 or 14 days of ven. But I think more and more as we’re doing these triplets or we’re doing combos with FLAG-IDA or with CPX or with gilteritinib, that theme is consistently emerging, but probably 14 days or less of ven is sufficient. And if you look at the pre-clinical data from 10, 12 years ago from Marina Konopleva, Tony Letai, others, I mean, that really is what was suggested because it’s assimilation of apoptosis. You’re not trying to have a continuous receptor saturation or occupation like an antibody or like a FLT3 inhibitor. You just need to get above that apoptotic threshold and get apoptosis.

Naval Daver:
So I think we’re getting there slowly. Of course, the label has the issue of saying 28 days, and so to move away from that you really have to show robust data, but as you said, with the ven-gilt response rate overall being very, very high (85%), and also in people who had prior TKI which is now really all patients in our centers. Everybody has prior TKI with induction, still maintaining around exactly the same. But, the true CR/CRh rate is only about 30%, which is about similar to gilt alone. And then you have this 40, 50% marrow remission. And the good thing is we have things like PCR for FLT3 and we could see that the PCR clearance was double of what we get with gilt alone, and if you want to take a patient to transplant, well that’s good enough. But if you’re thinking about using these doublets and triplets as standalone, as you said, maybe moving them up front, which is of course going to happen, I think a lot of effort and time needs to be spent in optimization of these regimens.

Naval Daver:
How much ven can we give? Do we do early marrow, document ablation clearance of the disease? Stop the ven, use growth factors early on? In a lot of these studies both doublets and triplets will be looking at that. But I think in the end of the day, these are regimens that are here to stay. They will move forward. Hopefully we can optimize them before people in the community kind of, because you and me and Amir and David, we know, but I think the community my worry is somebody gives 120 of gilt continuous and ven 400 continuous, and guaranteed, everybody will be absolute neutropenic and myelosuppressed. So, I think that’s kind of going to be the onus on us to get this data optimized, presented, published and highlighted soon.

Naval Daver:
But let’s move maybe to another emerging topic in AML: immunotherapy. So, you know, five or six years ago, early signs and interest but nothing really sticking and showing great activity. We were doing a lot of work with PD-1, CTLA4. I know others here have been also working on different immune antibodies. But now I think we’re starting to see a little bit more clinical translation of these datasets. So I think David briefly mentioned magrolimab. I think that would be a great drug to discuss, and David presented the data on that. So David, can you just highlight some of the key findings in both MDS AML and where you see magrolimab going, and how do you think it will be used? As a doublet, as a triplet, once, let’s hope, it’s approved?

David Sallman:
And so I think I mentioned briefly the P53-specific data. We had a small subset that we presented at ASH in wild-type patients, was 16 patients, but really very similar response rates across molecular subsets. And actually the median follow-up on that small cohort is a little bit more mature. It was over a year, and median OS in elderly, unfit population is 18 months. I think kind of similar to what we’ve seen with some of the earlier HMA, you know, venetoclax-based studies. I think small subsets, but very clearly I’m also excited about moving towards triplet therapy in patients, of course, if toxicity is not of concern. And I think what’s nice at least with magrolimab is we do get on-target anemia which can be a major issue in cycle one, and we need to keep these patients at a higher transfusion goal during that month for safety. But we don’t really see a worsening neutropenia or thrombocytopenia toxicity and thus may combine quite nicely as a triplet-based regimen given we have sort of a new standard of care with HMA-ven.

David Sallman:
So I know you have an investigator-initiated study on this topic, but I think there’s significant interest for pursuing this more broadly. I think maybe the focus of this call, of course, is AML, but I think we need to be very cognisant of the developments of MDS because they really impact each other significantly. Of course, ven and MDS has a lot of ongoing study. So the trial currently has breakthrough designation for high-risk MDS and really fully accruing a quite large expansion cohort. And again, response rates have also appeared to be very durable. You know, we presented updates most recently at ASCO and EHA, so I think as that agent may be further developed and approved, it may have other implications including off label. And I think at the same time, although we don’t have too long to discuss it, I mean, some of the other agents, pevonedistat had another updated presentation, at least had an event-free survival benefit in high-risk MDS and there are triplet trials with pevo and HMA-venetoclax ongoing in AML.

David Sallman:
Similarly, sabatolimab which is a TIM3 inhibitor targeting leukemic stem cells as well as augmenting adaptive immunity, some early data presented by Andy Brunner, with higher response rates. I think really a key question is durability and really longer follow-up is needed given the overall response rate and true CR rates are a little bit lower. And I think that’s probably a good summary, but I think one question I would have for the group is, just thinking of how do we really move these agents forward and what trial and what endpoints are critical? Because clearly there may be a lot of off label usage as Eunice was mentioning earlier, and how to safely guide that. So, open to discussion, but something I think it’d be nice to comment on.

Naval Daver:
Yeah, I think that’s a great one. Eunice, I mean, this is going to be, it is a major challenge, right? Even at big centers like ours, like MD Anderson and others, where we used to be able to do all the trials, we cannot anymore. There are just so many drugs. There’s so many trials and there’s so many combos. So are we still going to have these large randomized Phase III’s going on for years, or are we moving more to solid tumor or myeloma approaches where you get signals, PFS, OS? And we proceed. So Eunice, what are your thoughts with venetoclax, magrolimab, maybe other FLT3? How can we optimize these trial designs?

Eunice Wang:
So I think that we are in the era of targeted therapies, so the old gold standard where we were going to wait 10 or 15 years like the RATIFY trial, for readouts of overall survival are, we know now, probably faulty. We also know that in contrast to our solid tumor patients, that when patients relapse we have other options and for example we transplant them. So that’s always a huge confounder when you look at the data. I think that the fact that we’ve had a few agents, and I’d specifically highlight the INH1, INH2 inhibitors which were beautifully presented by Ari Melnick and Courtney DiNardo, their development over the last few years, really I think that we are now approving agents based on molecular precision targeting and I think event free or progression-free survival. We’ve also moved away from CR to CRC or CRI or CRH, or whatever the CR criteria is, as a response, given the myelosuppression.

Eunice Wang:
And as you mentioned in your trial, using molecular endpoints looking at variant allelic frequency, looking at MRD, there was a trial demonstrating that we have a correlation potentially between MRD positivity and overall outcome in patients treated with the oral azacitidine inhibitor. So I do think that we’re moving towards more flexible endpoints which are more relevant. That being said, I do think that we need to be careful, so I do want to caution one agent, the oral azacitidine which we were very excited to have as our first maintenance strategy for the treatment of AML patients having endured induction and/or consolidation intensive chemo but can’t move on to a transplant. That particular agent, the questions in the community are, can I substitute oral azacitidine, CC-486 in place of parenteral IV or subQ HMA? I’ve had questions, can I just use venetoclax and CC-486 in the upfront setting for my elderly patients so that I don’t have to combine those agents? And I think there needs to be some caution with that approach. It must be made clear that CC-486 is not the same equivalent. It’s a 14-day daily oral pill taken out of every 28 days in patients that have normal counts, or count recovery after intensive chemo. It is not to be used as a replacement. It’s not a one to one. No studies have been done.

Eunice Wang:
And as you said, I think the myelosuppression with these pills can be significant. So when you look at the other major question I get from the community, is, oh my God, this is so much more myelosuppressive than giving aza alone. So I think that we are moving into a target era. I do think we’re going to be more nimble. We’re going to use progression-free survival and use CRI and MRD measurements, but I think there’s a lot that needs to be done. And I think caution should be exercised and if patients are not able to travel to larger centers like us, it is always able to do a virtual visit now, or to speak with those individuals on the phone to get some guidance before the patients end up in the emergency room with a platelet count of 3.

Naval Daver:
Yeah, no, I think this is very important. I mean, you know, at the same time we’re kind of battling two fronts, where we’re hoping for early efficacy and molecular and MRD clearance’s approval, but at the same time I almost feel that, and we had this discussion in another call a few days ago, that these are going to actually make it harder for people in the community to treat AML. And I think there’s almost an ironical reverse feeling that, oh, you know, I can give oral CC-486 venetoclax gilteritinib and the patient will be great. Actually, I would be scared to give that combination myself even at a large cancer center. And I think in fact what’s going to happen, or should happen, is like with myeloma, is they start having these bispecific antibody CAR-Ts. In fact, the referrals have increased back into the large myeloma centers, and I think for AML as we trial these doublets, triplets, we hopefully will get more referrals and not too many people trying it at home and having 50, 60% early mortality which is, unfortunately, as you said, we get this question all the time. Why can’t I just do CC-486 ven? CC-486 gilt? And I say absolutely, there’s no safety data. Even I wouldn’t do this off a trial setting.

Naval Daver:
So yeah, there are going to be competing risks of, let’s move this forward, we have 9, 10, 11 drugs now, versus, is this really safe. You know, just because it’s oral doesn’t mean it’s safe. So, Amir, there was a lot of data also on bispecifics. I will kind of move the topic here, because I think this is another challenging area that for the last four years, many people have been working on. Yeah, some activity, but no clear path forward. There was data on flotetuzumab as well as XmAb presented. What’s your take? I know you’re participating on these studies. Do you think it has a path? Where will you use it? Can this be ever taken outside of academic centers into community? What are your thoughts there?

Amir Fathi:
Yeah, so the data on flotetuzumab has sort of been slowly emerging the last few years, and you yourself have been involved with ImmunoGen bispecific agents. They’re active. They’re active agents. We know that. We target different proteins, CD33, CD123. It seems that there is a gradual acknowledgement that there is a patient population that may benefit the most, and those are the refractory, early relapsing AML patients that for whom there might be a niche of effective drug development strategy for these agents. The data that’s been recently published and presented shows that they have a fairly decent composite remission rate, roughly around 30-something percent, with a fairly decent median overall survival for patients that are primary refractory or early relapse who historically have dismal outcomes.

Amir Fathi:
So it may be that such agents, particularly flotetuzumab, has a role in that subpopulation of patients, but as far as treatment in the community, I stand a bit skeptical about that, because I worry about the side effects, the marrow suppression, the CRS and the potential need for escalation of clinical care, critical care. So I think it’s difficult to say that this is a community drug, and I think that my general advice would be if you’re considering this for patients, first of all, they’re only available in clinical trials now. But if they ever become available more broadly, I would recommend their use just as with CAR T-cells, in an academic setting that knows how to best manage these patients.

Amir Fathi:
But in general I agree with my colleagues. There’s so many, and you and I wrote a review paper on it which was quite extensive and long, there’s so many of these drugs now, antibody-drug conjugates, naked antibodies, bispecific, DARTs, and very few of them, maybe except magrolimab, have a real established role yet in MDS and AML. And I don’t see a very clear one on the horizon. But nevertheless, I see some excitement. I think I like CD70 as a target, CD46 has established itself as a really impressive target. There’s some exciting CAR-T stuff coming out. David knows this very well. But I think we still are a bit away from that.

David Sallman:
Yeah, I think just along the lines of the flotetuzumab, you know, we call this a primary refractory patient population, but it is picking out a molecular subset. So I think from Ravandi’s presentation as well, the low blast AML, PD-1 low T-cell subsets, if you look at our recent Blood publication as well as the Blood Advances, flotetuzumab, you know, this may be picking up for P53 that we know are enriched in primary refractory acute leukemia, and so they may have this infiltrated picture that may be improved with therapy such as flotetuzumab. So that’s really important, clinical versus the molecular subset that we’re looking into.

David Sallman:
I guess my only pessimistic look at the data is, in patients, the durability of responses are extremely short-lived if you don’t go to transplant. I think there was a question to Dr. Ravandi from Elihu Estey saying what is the definition of durability, which was an interesting question. But I think a lot of this is in weeks to several months, and I think understanding that is critical. Now, [inaudible] to transplant is it’s own important candidate of trials, but there are other agents. So I think we just have to look at this further. It’s a lot of time in the hospital, potential toxicity, to think about durability. Of course, these are patient groups that have nothing, so I think we need to be, I think we can be optimistic. I’m open to other thoughts, but that’s been my concern, has been the durability of some of these agents which for a novel IO I would hope would be better than it is.

Naval Daver:
Yeah, I mean, I agree. I think that for the challenges we have to go through with 14 to 18 days hospitalization, you know, getting a 35% or so response without durability is going to be tough. But I also think that we’re not, and this is partly because of the regulatory landscape and what was allowed and not allowed, we’re not using them where we should use them, right? We have 10 years now, plenty of experience, where we know the best activity is in that low burden, MRD, early salvage, fit T-cell population, and we really never have been able to try any of those five BiTes in that setting. Now finally I think some of them are moving there, and I think that will be the real proof whether it works or not. I mean, if we do see low burden MRD disease, high clearance rates, better safety which you would expect because there’s less disease antigen, and a maintained profile, absolutely. If we don’t, then, well maybe it’s just not the way it’ll work for AML, and ALL of course is much more homogeneous, much better differentiated antigens. You know, hard to say.

Naval Daver:
But yeah, I think it’s an interesting area emerging. No clear winner, as Amir said, at this time among those. Magrolimab and flotetuzumab I think are quite exciting based on the data. Also important to note they’re front line, and then this is also different where we can have a clearer signal of activity compared to these single agents and in the salvage setting. So I think we have a few more minutes. Let me discuss FLT3, and Eunice has done a lot of work on FLT3. There were some data looking at maybe different sequential approaches, so people who have had prior induction with TKIs and then get FLT3. I think there were three different orals looking at that approach. What is your take on that, Eunice? Is that somewhere where you think that you’re still seeing reasonable activity with second generation? Would you consider doing single agent, or just really more combos? And how should we use this for further drug development?

Eunice Wang:
So I think that, I’ll talk about the retrospective data looking at sequential use. So as we all suspected and we all have had anecdotal experience with, the more heavily pretreated the patient, whether it be chemotherapy or a FLT3 inhibitor, the worse they do because of mechanisms of resistance. And there was a lot of data presented at this year at ASH, as you said, about three separate oral abstracts addressing that. So in general the take home points are, yes, the first time you use a FLT3 inhibitor works the best. The subsequent second and third times you use it, it works less well. It clearly appears to be that, as in conjunction with that, that combining the three inhibitors with other chemotherapy or other drugs leads to higher response rates particularly in that second or third exposure that you’re getting to, and in general the data supports the use of the newer generation, quizartinib [inaudible], specifically over earlier multi-tyrosine kinase inhibitors such as sorafenib.

Eunice Wang:
Now, there was data presented by Sasha Pearl regarding the results of the ADMIRAL trial and the CHRYSALIS study specifically looking at patients with relapse and refractory FLT3 mutant disease and how they did with gilteritinib monotherapy after they had received prior TKIs. And I think towards the end of the ADMIRAL study, midostaurin was approved, and so increasing numbers of patients have been enrolled, or have been treated with gilteritinib who had received prior midostaurin that did not represent in the ADMIRAL, so in the majority of patients that are involved in that trial. So this was sort of an attempt to address that question, like if my patient got midostaurin up-front, could they respond to gilteritinib? And in general, the data, my impression was that there was a difference. I mean, the survival curves looked , though it was not statistically different when they were treated with gilteritinib with prior TKA. There was clearly a separation of those statistically when they combined both the data with CHRYSALIS which his the phase IB and the ADMIRAL trial. There was no difference in prior TKI usage. There was a small differential of 45% versus 51% in terms of response rates, and not statistically different due to small numbers difference.

Eunice Wang:
So I think that based on that, the preference would be using more potent inhibitors up front and using combination therapies and the abstract that highlights the feasibility in that is one that’s been very anticipated presented by Keith Pratz and colleagues, the results of the Phase I safety feasibility of gilteritinib added to 7+3 as an alternative or to midostaurin 7+3. So, gilteritinib may or may not work well, whether we want to debate that or not, in somebody that had prior midostaurin. Why not move the gilteritinib in place of midostaurin? So the trial presented by Pratz and colleagues did recognize that, looked at a couple different 7+3 backgrounds, idarubicin as well as daunorubicin as you recall, and the RATIFY trial there was daunorubicin only and it was 60 mg per meter squared, not 90.

Eunice Wang:
So overall the data suggested that it was feasible, 120 mg given for 2 weeks plus with the intensive chemotherapy in consolidation was acceptable. They did have some decrease in the duration again due to myelosuppression, as you pointed out. They couldn’t do 28 days of gilteritinib, however, I was again, it may also be because of myelosuppression. Again, the true CR rate was only about 30-40%, and you would have wanted all 80% of the patients to have a full CR and full count recovery. So, we have to wait. There’s two Phase III trials, one done in Europe and one Phase II ECOG study here in the United States, looking at randomizing patients to gilteritinib versus midostaurin, but there still is that question, as you highlighted, about myelosuppression, CR versus CRC, and again I thought the Phase I also brought up the question of, can you give idarubicin? Because it looked like they sort of gave up on that and moved back to daunorubicin as their baseline regimen.

Eunice Wang:
So I think that wasn’t as positive as we would have wanted to see, like a 95% CR rate and incredible tolerability. Not quite, but still very enthusiastic. I know a lot of us [will] look that again in an off-label, but again to be careful about the myelosuppression. So, more to come, but I think FLT3 inhibitors, second-generation combinations, use them up front.

Amir Fathi:
Just I-

Naval Daver:
Go ahead, Amir, yeah, please.

Amir Fathi:
But I just have to say one quick thing. So, the response assessments, CR, CRI, as we all know, they were developed in an era where there were really no targeted therapies. And what they ultimately meant that if somebody did not recover their counts that the likelihood of persistent leukemia as the accounting factor was very high. Nowadays when you give gilt and ven and all these drugs that have potential for myelosuppression, you do get a CRI, but what is that CRI? What’s the nature of that CRI? And I think that’s an important consideration because, you know, having a totally MRD negative CRI is very different than having a CRI after 7+3 for complex carrier type AML or MDS AML. You know, you worry about the latter. You also worry about the former, but for a different reason, for myelosuppression.

Amir Fathi:
So I don’t worry as much about the lack of response from these combination studies, because I think they’re real responses, and I’ll bet you that the responses are quite impressive. But I am concerned about combining a lot of [inaudible] together, as Eunice was saying, in terms of myelosuppression.

Naval Daver:
Yeah, absolutely, and I think this data, it’s not just without data. There’s data from Roland Walters very few years ago and now recently from Farhad Ravandi and Nick Short in a very large, the largest meta-analysis for MRD ever done. If you basically sum it up, the only thing that matters is MRD, right? If you have a CR MRD positive, or a CRH MRD positive, or a CRI MRD positive, it doesn’t matter. If you have a CRI MRD negative, it actually does matter. Those people actually do really well. So, I think that we’re not there, the FDA isn’t there yet, but I think we’re moving very quickly there, and I think FLT3 may kind of be the beacon that pushes it because, as you know, on one of the precog studies which is randomized, it is going to use FLT3 PCR at the end of two cycles as the primary endpoint. And again, it may or may not be a registration study, but I think if that study shows that and then shows that that was clearly associated with survival, I think at least for FLT3 for all these triplets, et cetera, and there’s already discussion, that will be the endpoint. Can you achieve molecular clearance with a 60-day mortality that is safe? And that really is all that matters. You know, let’s not worry about this CRH, CRI.

Naval Daver:
But, we’re not there. The FDA is not there yet. But I think we’re heading that way, just like in CLL and in ALL, others for MRD will be the key. But I think we’re out of time here. Thank you all very much. We could keep on discussing. You know, one of the topics we didn’t bring, but I do want to mention and give Eunice a chance to highlight, which I think is actually one of the critical early but important drugs is menin inhibitor. This is very important that we had FLT3 IDH who had TP53 directed drugs, and now we have a fourth potential very active target. So Eunice, you want to give us a brief update on this, and where you see this going?

Eunice Wang:
Yeah, so on behalf of my colleagues including Dr. Fathi who is here on this call, I presented some early data suggesting that a novel class of agents which were oral menin inhibitors, may have a role in future therapy of AML, particularly for those mutational subsets for right now that we don’t have a targeted therapeutic. So the KO-539 is an oral menin inhibitor and inhibits the interaction of menin with the MLL rearranged epigenome complex which is a key component of the pathogenesis of MLL, rearranged AMLs, as well as MPM mutant acute leukemias. Early data with this once daily oral inhibitor suggests that it’s very well tolerated at doses up to 400 mg. It doesn’t interact with CYP3A4 inhibitors, does not cause QT prolongation, and there were no drug discontinuations due to treatment-related adverse events.

Eunice Wang:
Interestingly enough in the first cohort which was agnostic of mutation, there were two CRs out of the first eight patients, and another four patients on the first eight that demonstrated some stabilization or clearing of blasts or morphologic leukemia free disease. And those patients had both MLL KMT2A rearrangement as well as did not have MPM1 or KMT2A rearrangement, suggesting that this could potentially be useful across different mutational subsets. Now, I want to caution, it is only a handful of patients, but there was early data presented with a similar agent, SNDX, earlier this year, also demonstrating in their very early studies that there were some clinical responses. So this is an area that we’re going to be looking at pretty closely. The combinations I think are going to be key, but also waiting until we get a maximum tolerated dose and expanding this out to get a real sense of that efficacy, but I feel that even if the efficacy isn’t as good as we’ve seen already, this might be a great partner to add on to other therapies. As we know, Dr. David was mentioning, the P53-targeted APR-346 drug which name I cannot pronounce, like you guys, was really seen in combination with azacitidine, and magrolimab, the CD47 antibody, similarly had low efficacy as a single agent, but really has come to the forefront as a potential new standard of care in combination with azacitidine. So I think more to come on that.

Naval Daver:
Yeah, absolutely, and I would say at Anderson as well. We’re involved with both SNDX. We’re very, very excited. We’ve seen some of these responses, dramatic 7, 6 salvage kind of patients who had nothing else, and seeing this, very reminiscent of IDH days, when we started having those and even before that, gilteritinib, quizartinib days. So, I agree. I think this is real, but it will probably be enhanced even more as we move it up front with the best combos. And MLL is an adverse risk feature, so even more important. And of course, ALL, I think this could be a major player as well. So very exciting data emerging from there.

Naval Daver:
So with that, I think we’ll close it out. Thank you all so much for joining and discussing this, and have a great day. Thank you.

Eunice Wang:
All right. Take care.

David Sallman:
Thank you.

Eunice Wang:
Thank you.

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AML post ash podcast

Disclosures

David Sallman – Advisory Board: Abbvie, Agios, Aprea, BMS, Celyad, Gilead, Intellia, Kite, Novartis, Syndax. Consultant: Magenta. Speaker’s bureau: Agios, BMS, Incyte. Research Funding: Celgene, Jazz

Naval Daver – Research funding: Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE, Amgen, Novimmune, Glycomimetics, and ImmunoGen. Consulting or advisory role: Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen and Agios

Amir Fathi – Consulting fees: Boston Biomedical, PTC Therapeutics, Agios, Celgene/Bristol-Myers Squibb, Abbvie, Astellas, Novartis, Daiichi Sankyo, Trovagene, Seattle Genetics, Amgen, Pfizer, NewLink Genetics, Jazz, Takeda, Genentech, Blueprint, Kura Oncology, Kite, Amphivena, Trillium, Forty Seven/Gilead. Research funding: Celgene/BMS, Seattle Genetics, Takeda, and Agios

Eunice Wang – Advisory board: Abbvie, Astellas, BMS/Celgene, Genentech, GlaxoSmithKline, Jazz, Kite Pharmaceuticals, Macrogenics, Novartis, Pfizer, PTC Therapeutics, Stemline, Takeda. Speaker role: Stemline, Kura, Pfizer, Dava Oncology. Data monitoring committees: Abbvie, Rafael Pharmaceuticals

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