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Welcome to The AML Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Naval Daver and Eunice Wang, who debate key updates in FLT3+ AML from the 2021 ASH 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 and Eunice Wang, who debate key updates in FLT3+ AML from the 2021 ASH meeting.

The topics of discussion include combinations, triplet regimens, and other novel agents for FLT3+ AML.

Combining agents for the frontline treatment of FLT3+ AML

 

“Could we add a FLT3 inhibitor for treatment in these patients and improve overall survival? Now the ultimate analysis showed that there was no difference in overall survival between the patients getting gilteritinib-aza versus azacitidine alone.”

– Eunice Wang

Moving towards triplets and fully oral regimens

 

“At MD Anderson… we are putting some form of triplet on trial, but is it ready for primetime community use? I don’t know. I think we still need more mature data.”

– Naval Daver

Other approaches to FLT3+

 

“When you look at the Phase II studies, all of the newer generation FLT3 inhibitors have overall CR rates of 80% or better as opposed to 55%, 59% with midostaurin. So I cannot imagine that I would be very surprised a 20% difference would not be born out in some of these Phase III trials that are ongoing right now. I think with that, we’ve had a nice discussion on FLT3 and hope you all enjoy the meeting and a lot of other things that will hopefully come out for AML and ASH, and thank you very much..”

– Eunice Wang

Watch the full session
Full Transcript

Naval Daver:

We’re here at the ASH 2021 meeting. It’s a great pleasure to be here discussing some of the hot AML topics with my friend and colleague Dr Eunice Wang. So one of the things that I think at this ASH, there’s a lot of data emerging on is different therapies for the FLT3 mutations. So, of course, we have the established single-agent FLT3 inhibitors and salvage but now there’s a lot of effort to combine those, whether it’s in the frontline or the relapse/refractory setting and Eunice you’ll be presenting on the aza + gilteritinib versus azacitidine frontline data. So, as the lead author on that, and a lot of experience in the FLT3 space, what are your thoughts on frontline development for FLT3 inhibitors? Do we incorporate these with aza-ven? Is there a role for aza FLT3? Are we still going to use aza-ven? What are your thoughts?

Eunice Wang:

I think up until now, the treatment for patients with FLT3 mutant disease has been suboptimal. We do know that venetoclax-azacitidine works very well in that patient population, but we also know through subsequent studies that the FLT3 three mutation can be a mechanism of therapy resistance, and failure to ven-aza. And that some patients who have FLT3 mutations are going to have shorter response times. I think there was some data from MD Anderson saying that patients, for example, that had FLT3, ITD mutations with high allele burden may not have benefited as much from ven-aza as other subcategories. So the lacewing study being presented here is a study, which was halted in the interim analysis.

Eunice Wang:

It was randomizing older unfit patients who could not get intensive chemotherapy to either gilteritinib, which is a new generation FLT3 inhibitor used in the relapse setting and azacitidine versus azacitidine alone. This study was initiated prior to the approval of venetoclax azacitidine and that did not represent a standard of care at that time. So the question was, could we add a FLT3 inhibitor for treatment in these patients and improve overall survival? Now the ultimate analysis showed that there was no difference in overall survival between the patients getting gilteritinib-aza versus azacitidine alone. However, there were some important lessons that we saw, for example, the overall response rate of patients who received gilteritinib-azacitidine was 58%, and that compared very favorably with less than 20% in the aza alone group.

Eunice Wang:

We also saw that patients that had that FLT3-ITD allelic ratio that was very, very high, seem to have significantly longer event-free survival than patients that had azacitidine alone and patients who were fit enough and were not having low performance has also appeared to benefit and have more or prolonged event free survival with the gilteritinib-azacitidine combination, also importantly, there was no new safety signal, so we didn’t see any new side effects or tolerability, both groups tolerated it fine. And interestingly enough, when you look at the patients that get azacitidine alone, a number of them when they didn’t respond to the azacitidine, then went on to get subsequent therapy. And a number of those patients actually went on to get subsequent gilteritinib.

Eunice Wang:

So we don’t know whether the addition of gilteritinib in a sequential fashion could have muddied the waters in terms of that being a true control group, when you look at overall survival. The lessons we’re going to do, and I, think Naval, your group at MD Anderson and yourself have been involved in newer therapies triplets. So I don’t know if you want to talk a little bit about some of the triplet therapy that you and your others have been doing.

Naval Daver:

I think just to get back to your point, I think this is an issue we’re going to see across the board in AML is, now that we have good salvage options and we saw this with the azacitidine-enasidenib randomized study too, that even though azacitidine-enasidenib more than double the CR double the EFS, the worse was the same. And that was because people got salvage with venetoclax or IDH and relapse, and so I think the OS endpoint itself now is very questionable. Something that multiple myeloma, for example, 10 years found out and moved on to like PFS or MRD clearance or CR because, you can salvage these people, and as you said, the gilteritinib given later may have muddied the outcome. So, I think the big question, as you mentioned, is aza venetoclax, frontline new standard, but survival is less than 12 months in the frontline for the FLT3 subset, that’s a subset of course it’s not randomized for that, and so question is, can we improve on that?

Naval Daver:

And really the first step was we did a venetoclax-gilteritinib study that you’re aware and familiar and have worked on, and that in the relapse setting is showing very, very good response rates, close to 80% CRC with about 60% of them with FLT3 molecular clearance. So that made us feel confident that pre-clinically the synergy of venetoclax FLT3 is now being mirrored in the clinic. And then the next step was, can we move it frontline? And we have a couple of presentations here from Dr. Short in our group and from Dr. Yilmaz also in our group where we’re now looking at combination HMA venetoclax with gilteritinib, HMA venetoclax-quizartinib the so-called triplets and, no doubt the remission, as well as the molecular clearance, the true CR rate, all of those look much better, again, comparing it within institution to our experience with HMA and HMA FLT3, but there is increased myelosuppression.

Naval Daver:

I think that’s going to be the question is, how to balance it. I think for big sites that have very good monitoring, blood counts, you can do labs three times a week, prophylactic, anti-bacteria’s, antifungals, a lot of expertise, dose adjustments of VEN I think that’s a great option, and for us at MD Anderson, all our frontline, we are putting on some form of triplet on trial, but is it ready for primetime community use? I don’t know. I think we still need more mature data. We need more follow up, and eventually, I think we need some form of maybe randomized Phase two or larger multicenter experience with that, whether it’s with HMA van gilteritinib or HMA ven quizartinib. But I do think that there is a potential for that to become a very effective approach in the future.

Eunice Wang:

I think so I think that’s great. I mean, we have all these tools in our toolbox. We should combine them. Do you think that there might be down the line just like we do in intensive chemotherapy, maybe like an induction phase where you get like all three drugs and then once you clear maybe some maintenance strategies maybe with these oral agents. There’s a lot of ways that we can tinker with this to make it something that is more tolerable, but I think that seeing 80, a hundred percent response rates in acute myeloid leukemia, unfit patients not getting intensive chemo is so I think a game changer that’s something that we wouldn’t have imagined a few years ago was possible, and I think combining targeted and low dose therapy is really, really changed things in our perspective.

Naval Daver:

And as you said, there’re more things we can do there, oral options coming out. So of course you have to look at them in trials, but could we have, three, four years from now a fully oral regimen, oral decided being venetoclax-gilteritinib for a frontline, FLT3 AML with, like you said, 80, 90% response MRD clearance. I mean, if you look 10 years ago, I don’t think anybody would’ve bet their money, that we could potentially even think of that. So you’re not there, but maybe, maybe in the future.

Eunice Wang:

I think there’s a lot of interest and enthusiasm. I think my patients ask me almost every day, is there an oral azacitidine they could take with the oral venetoclax, two pills to get their leukemia into remission and to keep it in remission, we add on a third pill, a FLT3 inhibitor, and I think that you should all stay tuned because I think in the next couple ASH meetings, we’re going to start to see more and more of that.

Naval Daver:

As you said, when we talk about these triplets, whether it’s a true triplet long term, which I think is very difficult to deliver, we have the experience with that. Or as you said, is it an initial push, get molecular clearance, MRD negatively, and then you move to something. And the good thing is, we are all working on these trial designs and hopefully we’ll have more information in the future. Also, I think in the FLT3, it’s important to mention, although there’s no data at ASH, but we know that quizartinib, which we’ve all worked with and think is a very powerful drug. We just now had a press release few weeks ago, showing that in the frontline setting, quizartinib added to intensive chemo appears to improve the overall survival primary endpoint.

Naval Daver:

We don’t know the details, those will hopefully be public in a few months, but I think this is great news because just like CML, the more TKIs we have, the more selection, some patients have GI issues quizartinib could be better. Some have cardiac, gilteritinib could be better. You’re working on crenolanib, maybe you want to mention what’s happening, where that’s going.

Eunice Wang:

I think that there’s a new generation of these FLT3 inhibitors of which gilteritinib is the poster child for. Much more potent, much more specific targeting specifically the mutant FLT3. I know there’s even newer ones in development now as well.

Eunice Wang:

I think these newer ones are going to replace midostaurin because midostaurin is really a drug that was developed, I would have to say probably 10, 15, more than that years ago. It works. The fact that it works in induction chemotherapy and enhances a result is impressive. But now that we have specifically rationally design FLT3 inhibitors, I see all of these newer FLT3 inhibitors, potentially some planting midostaurin. And we’re already, as we saw with the quantum first study, although that didn’t include midostaurin, starting to see that data emerge, when you look at the Phase II studies, all of the newer generation FLT3 inhibitors have overall CR rates of 80% or better as opposed to 55%, 59% with Midostaurin. So I cannot imagine that I would be very surprised a 20% difference would not be born out in some of these phase three trials that are ongoing right now.

Naval Daver:

I think with that, we’ve had a nice discussion on FLT3 and hope you all enjoy the meeting and a lot of other things that will hopefully come out for AML and ASH, and thank you very much.

 

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Disclosures

Naval Daver – Pfizer, Otsuka, Novartis, BMS, Incyte, Sunesis, Karyopharm, Jazz, Daichi-Sankyo, Abbvie, Glycomimetics, Servier, Genentech, Covance, Immunogen, NOHLA Therapeutics, Agios, Sobi, Astellas, Hanmi, Forty Seven, Newave, Trovagene, Celgene, Amgen. Research Funding: Pfizer, BMS, Novartis, Daiichi-Sankyo, Karyopharm, Incyte, Abbvie, Sunesis, Servier, Genentech, NOHLA, Glycomimetics, Immunogen, Sobi, Astellas. Hanmi, Forty Seven, Newave, Trovagene, Covance, Amgen. Advisory/Consulting: Pfizer, Novartis, BMS, Otsuka, Celgene, Incyte, Jazz, Karyopharm, Sunesis, Immunogen, Abbvie, Astellas, Daiichi-Sankyo, Agios. Honararia: BMS, Jazz, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas, Abbvie

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