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- [00:02]
Host
Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Selina Luger discusses the review series titled Spotlight Series on Acute Myeloma leukemia with authors Dr. Laura Michaels and Dr. Alexander Sasha Pearl.
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Dr. Selina Luger
Dr. I'm Dr. Selina Luger and I'm here today with some authors from our Spotlight series on AML that was recently published in Blood. And our goal for this series was really to think about some of the major challenges in treating patients with acute myeloid leukemia. Today we had four articles in this series, each one of them addressing a different topic that we consider a challenge. With us Today we have Dr. Alexander Pearl who focused on approaching FLT3 mutated AML. This has for several years been a challenge for us early on because it was a very high risk disease that we did not know how to approach. Now, fortunately, because it's a disease in which we have several treatment options still with decisions that need to be made, we need to think about how to approach those challenges. We also have with us Dr. Laura Michaels, who together with Dr. Abedin and Dr. Wee talked about the fit older adult with AML and the clinical challenges in providing care to that group of patients. Also in this series with two additional articles, Dr. Roland Walters Potter and Charles Craddock talked about allogeneic transplant in patients over the age of 70 with AML. And Dr. Salman and Dr. Stahl talked about TP53 mutated AML, which is really a challenge for all of us in the older and younger age group and a serious challenge in our population these days. And so I'm happy to present Dr. Pearl and Dr. Michaels who will be discussing their publications today. Dr. Michaels, can you tell us a little bit about your article and what you think the take home messages are?
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Dr. Alexander Sasha Pearl
Yes.
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Dr. Laura Michaels
Thanks so much. This was indeed a challenge to write because when you think about the older fit patient with aml, the first point we wanted to make is a lot of the developments that have occurred in the AML community for patients have been specifically directed to the less fit patient. These include, of course, the foundational change in treating individuals with a combination of BCL2 inhibitor venetoclax with a hypomethylating agent and as well as many of the targeted agents which again have been agents like IDH2 inhibitors, IDH1 inhibitors, even some of the FLT3 inhibitors have initially moved into the clinics through trials that focused on a less fit or a more frail individual. And so the older adult, with the exception of using liposomal donorubicin and cytarabine. The older adult who's fit hasn't really been eligible for some of those benefits. So that's the first point we made. The second point we made is that for years, and those listeners know this better than anyone is, there's been a lot of spinning of our wheels on how do we even know if somebody's fit or not. So we summarized a little bit where the state of the art is on frailty measures, geriatrics assessments, and the difficulty in proving those to be clinically relevant because of the absence of randomized data. One of the key third points that we made in our article is that really the question of fitness goes away if therapies that are less toxic are proven to be just as efficacious in the older fit age group. That entails randomized trials that randomize individuals to intensive versus less intensive therapy for the same disease type. One of the points we made is to take a look at there have been published articles, including one from your institution, that look retrospectively at individuals that might be somewhat matched according to disease characteristics who were treated with either hma, Venetoclax or for example, cpx. And so those have shown similar remission rates and very similar overall survival rates. But again, those are biased by being retrospective. There are right now three randomized prospective studies that are taking individuals that are older than 60 and flipping a coin about whether or not they're treated with one regimen versus another. We will see where those turn out. And indeed that might be one thing that makes the entire assessment of fitness less relevant. If we know that we can treat them the same way. Then finally we looked in our article at some of the ways to understand the appropriateness of response in an older patient, somebody where the disease hasn't come up, the disease has maybe grown up in a marrow niche which is much more likely to relapse. And how do we really judge remission? How do we know that we've got enough done? So those are some of the things that we talked about that we addressed in the Spotlight article. I think there's a lot of questions answered, not a huge amount of answers, but it was really helpful for me at least to to identify some of the stuff that you face when you've got a 65 year old, very healthy person sitting in your clinic with aml and why that feels like such a series of fraught decisions.
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Dr. Selina Luger
Do you think that ultimately the goal for all older patients is to get them to transplant if they're Fit well.
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Dr. Laura Michaels
It depends on the disease characteristics. I think that there are some individuals that are older that we may be able to cure with chemotherapy alone. The rare individual with the core binding factor leukemia, and potentially individuals with genetically intermediate or favorable risk aml, where we can accurately follow MRD and ensure that a true remission is really a true remission. Maybe those people can be salvaged at first relapse and therefore can avoid a transplant, but certainly better ways to understand the depth of remission. I thought one of the nice follow ups in the CPX versus in the retrospective study of CPX was the fact that individuals that got to transplant either a less intensive or more intensive route still had equivalent survivals.
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Dr. Selina Luger
One of the things that comes up very often when we speak to physicians who treat leukemia is they feel that they need to treat the patient the minute they come into the hospital because acute leukemia is acute leukemia. Do you think that's still the case?
- [06:57]
Dr. Laura Michaels
There is growing amount of data that that's not the case. We knew initially that there was a study, I think out of Cleveland that said that the older patients, you can wait. And now I think there are similar studies that also verify for younger patients. There are certainly a few patients where you have to treat them right away or at least stabilize them right away. But I think we've Learned from Beat AML. We are hopefully going to learn from MyLamatch that people can generally wait until we get a full panel. I think our diagnostics need to speed up so that you're not sitting somebody in a hospital for a week and a half waiting for numbers to come back. That's often one of the problems is, oh my gosh, send her to the er and then we sit there and wait with them for a week while we're trying to figure things out. But from a safety stake, I would say the great majority of patients with aml, you have time to get the foundation right. And that's what I often. I mean, I'm sure all of us tell patients is it makes difference. And as these things move closer to the front line, rather than waiting to day 8 or day 14, we may be we need to be giving that to them on day one.
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Dr. Selina Luger
And since we have the two of you here and not the others, tell me a little bit about how P53 impacts your older FIT AML patient, at.
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Dr. Laura Michaels
Least in our practice here. P53 first off, we don't usually use cytotoxic chemotherapy or traditionally cytotoxic chemotherapy for p53 mutated disease. We will usually first and foremost look for a clinical trial if there is one, and then in a P53 mutant patient would probably use less intensive therapy. We haven't rolled into using the metronomic type of treatment where you're giving it even less frequently as a standard. There's sometimes we discuss that in our tumor board as a potential. I think if there's any place we need progress, it's how to treat this disease. We still, at least in our hands, will take a patient in remission to transplant with P53. But I know that there are some arguments that these patients are, aren't necessarily benefited by transplant. So the most difficult thing I think also is that even when you can get somebody in remission with P53, that doesn't necessarily translate into an improved overall survival.
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Dr. Selina Luger
Thank you so much, Dr. Pearl, you gave us a nice summary on FLT3 mutated AML. Can you give me a little historical perspective on how we've gotten to where we are today with FLT3 mutated AML?
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Dr. Alexander Sasha Pearl
Sure, happy to. FLT3 is a receptor tyrosine kinase. It's mutated in about a third of patients with aml and it really is essentially the first target for which we had drugs that were approved that we would use a mutation diagnosis and give the patient a targeted agent in the hopes that this would improve their outcome with standard chemotherapy. The Ratify study was the first example where we had a new drug approval that was for a mutationally selected population. And the drug that was used, Midastorin, is actually a pretty old non selective kinase inhibitor that was designed to inhibit kinases generally and wasn't a very specific or selective FLT3 inhibitor since that drug was developed. There are a number of kind of newer drugs that are much more selective for FLT3. These include Quizartinib, Gilteritinib, that were not so much a FLT3 inhibitor by accident, but more by design. And those drugs seem to have more activity in the relapse and refractory setting, which is where gilteritinib is approved and quizartinib has joined Mitastorin as being an approved therapy frontline. So in patients with FLT3 mutations, we actually have several agents that we can use that target the FLT3 kinase, turn off its function and in doing so either make chemotherapy work better or in the case of gilteritinib in the relapsedrefractory setting have outperformed salvage chemotherapy in a head to head comparison trial. So these drugs have significant activity They've led to improved survival in both the frontline and the relapsed refractory setting. And importantly for patients who have FLT3ITD mutations, who historically have had generally very poor outcomes, those patients generally have done much better when they've gone to transplant. And it not uncommonly was the case in days of old that we wouldn't get those patients to transplant. They would actually go into remission, fall out of remission, relapse before they would be transplanted. And it was very hard to get those patients back into a remission again. And long term survival was rare. So there was a real onus to quickly get the patient to transplant and, and then often to add back a FLT3 inhibitor, if you could get one, in hopes that it would prevent relapse. And we didn't have a lot of data back then to say that that was the right thing to do. Fast forward to where we are today. We have lots of phase three data to say what's the right way to treat patients who have FLT3 mutations, whether it's FLT3ITD, FLT3TKD with intensive chemotherapy, with transplant after transplant. In the salvage setting, we have so much more data that we really have an evidence base for how best to treat patients. And that's largely what I wrote about in the spotlight on Flit 3 is now that we have all this data, how do we put this together to best treat our patients? And is this maximally intensive approach really the best one now that we're starting to see the patients are doing better and may do better with even less therapy? And lastly, how do we measure how well patients are doing? We can estimate that based on the quality of their remissions, which for FLT3ITD, we have some new tools to use, including MRD, that looks at the burden of FLT3ITD mutation for patients in remission, and we can use that to quantitate how much residual leukemia is present in a marrow that morphologically has no visible leukemia, we can see how much measurable residual disease is there to a very sensitive level. There's a number of studies that have actually shown that that's predictive of chemotherapy success, of transplant success, and also for the benefit of a FLT3 inhibitor given after transplant, where we now know from the morpho study that if we give a FLT3 inhibitor as post transplant maintenance for patients at first remission, there really is only a benefit seen in the patients who had peritransplant MRD as measured by one of these ultrasensitive assays. So we can educated estimation, say, what's the right therapy for a patient? Do they need a maximalist approach? Or can we think about maybe using less chemotherapy? Maybe this patient doesn't benefit so much from transplant. If they do go to transplant, do they need maintenance? And if they are having complications of transplant, do we need to focus more on treating the GVHD or making sure they stay on the FLT3 inhibitor? How long do they need to stay on the FLT3 inhibitor? Those are the kind of questions we can only answer when we can monitor patients for the quality of response. The last point, which kind of follows up on what Dr. Michaels was saying before, is now, for patients who have the option of intensive therapy, but might prefer a lower intensity therapy, we've got some very active regimens where we look at the backbone of venetoclax and HMA and add to that a FLT3 inhibitor. And it's similar to the story where we first added mitostorin to intensive chemotherapy. These are making those regimens achieve very high remission rates and very high MRD negative remissions. So this may actually translate into better survival for these patients. And of course, the only way to prove that is to do randomized studies. And those studies are actually already underway right now. We know a lot more than we used to, and I'm hoping in the future we really could say this is the right way to treat the patient at every step of the way.
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Dr. Selina Luger
So you talked about potentially using less aggressive therapy in the fit patient a little bit like Dr. Michaels did with the older patient. What about the older patient who is not fit? What do you think the questions we should be asking there are older patients.
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Dr. Alexander Sasha Pearl
Are actually kind of interesting bunch. We've done studies of intensive chemotherapy with or without FLT3 inhibitor, and to date we have not proven what we saw in the younger patients extends to the older patients. Meaning that adding a FLT3 inhibitor to intensive chemotherapy improves their survival. There's really only one study that's looked at that in a randomized fashion that was placebo controlled and it did not show in the subset analysis of the older patients that there was a survival advantage to the FLT3 inhibitor arm. That's the quantum first study with crizartinib. That doesn't mean that I never do that, or I would say that that's the wrong approach. But I think we may be able to do better by potentially using perhaps a more appropriate therapy for this patient population. Which is a lower intensity approach, meaning venetoclax and hma, which I think is actually generally a good regimen for older patients with FLT3 mutations. The problem being what we've seen in the past, that patients with FLT3C ITD have a high rate of relapse even when we do that. So it leaves us the question of, should we use that as a bridge to a transplant for these patients? Should we add in a FLT3 inhibitor? If so, do we have tolerable regimens that we can give in multicenter studies that outperform venhma alone? I think these are unanswered questions, and it's why we're trying to get a better sense of this through randomized studies. The myelomatch study that Jessica Altman and I are leading will randomize newly diagnosed patients who are not candidates for intensive chemotherapy to either venetoclax HMA or venetoclax HMA plus gilteritinib in one of two regimens to look at different sequences of adding the FLT3 inhibitor. And the idea of looking at different sequences is to try to avoid some of the toxicity that we've seen, which has been prolonged myelosuppression with that approach. So we think it's very impressive to see higher remission rates and potentially better survival. But we want to make sure that it's feasible and feasible kind of around the country as hopefully a new regimen that will become a standard therapy and not just something you need to refer a patient to a very specialized academic center.
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Dr. Selina Luger
Okay, now I'm going to ask you a question that has nothing to do with FLT3, but why can't we do the same thing for P53?
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Dr. Alexander Sasha Pearl
Well, P53 is a little bit different than FLT3, so it's not an activating kinase where we have a drug that turns off that function that's changed in the presence of the mutation. P53 regulates DNA damage repair, and we don't have a way to restore that once it's lost. So I think one of the challenges here is just we need the tools in the toolkit. We have several FLT3 inhibitors, and each drug is a little bit different, but they're all working on a common theme, which is the kinase is activated, which regulates hematopoiesis, contributes to differentiation block, promotes proliferation of the leukemia, and we can shut off those features with these drugs. We don't have a drug that does that for P53. There'd been interest in drugs that affected the folding and unfolding of TP53, which might have impacted its function. But unfortunately, those drugs in phase three didn't show that they were better. And a lot of different studies that have looked at various different ways that we could target TP53 mutated leukemias, whether it was immunotherapeutics such as macrophage checkpoint inhibitors, magrolumab being an example of this, and those didn't pan out in phase three. It's just been really hard to target this. I wish we knew the right way to do it. I certainly think there's a lot of smart people looking into this, smarter than me, certainly, and hope it's going to be the case in the future that we have both effective reagents and many of them because it's a really tough subgroup of patients. And unfortunately, it's. Especially in the older patients, it's relatively common.
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Dr. Laura Michaels
Sasha? Yeah, beginning with way back when with sorafenib, and now with three or four on the market, as you mentioned, where are we falling short? Like, what would this next generation of FLT3 inhibitors solve for?
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Dr. Alexander Sasha Pearl
Well, there's a few things that if you had to Design a perfect FLT3 inhibitor, you would want. You'd want it to be very active against the kinase. You want it to be really tolerable. You'd want it to play nice in the sandbox with all the other medications. And ideally, you'd want one that really just establishes itself as the drug of choice. And so there are some studies that are ongoing to say we have the option of using one FLT3 inhibitor versus another. In fact, Selena has led a study, the Precogo 905 study, that compared midastorin versus gilteritinib. To say, if you have a newly diagnosed patient, which one should you use? Is one better than the other? We're still waiting for some data off of that, but at least in terms of remission rates and MRD negative responses, we've not seen an obvious advantage of one over the other. So it would be nice to have a drug that just was head and shoulders better than the others in terms of efficacy. That would be a nice thing. What I like about Most of the FLT3 inhibitors is that they're generally pretty tolerable. And I think tolerability is really important, particularly for drugs that you take for more than, say, 14 days a cycle. Now that we're looking at longer maintenance therapy after either completion of chemotherapy or post transplant, I think that's an area where tolerability is important. And even a drug like gilteritinib that we think of as being relatively easy to give to patients, there are patients who have to stop it because of side effects. And there was a higher rate of infectious toxicity in graft versus host disease in the gilteritinib arm of the morpho study. So, you know, anything we can do that lowers the toxicity of these agents, makes it easier for them to be combined with other agents, whether it's chemotherapy, decreased myelosuppression, hopefully these are areas where we'd like to make those advances. And the last one is just to avoid resistance, which we were interested in developing a number of these drugs as to what were the mechanisms for resistance. And as single agents, they're probably different than in combination. As single agents, we would often see, say, with quizartinib in relapsedrefractory patients that there would be new FLT3 mutations. With gilteritinib, there would be activation of ras and MAP kinase mutations. But the big thing that we're seeing is we're just selecting for leukemia populations that don't have FLT3. And that's kind of emerging as what we're seeing as we add these drugs to frontline therapy. And I don't honestly know how to target that. Maybe that's not something we need to target. We just need to get more effective frontline therapies. So I think we're doing pretty well in terms of having tolerable drugs. And I think as we go further, there are a few areas that I can think of. You know, we could do this or that a little bit better, but we're doing actually pretty well with the new drugs. The last thing I might be interested in is are there drugs that have other mechanisms of action? There's been interest in combining drugs that attack Iraq four with FLT three, some drugs that attack jak. Whether these are advantages or disadvantages because they are other targets, I think still remains to be seen. But there has been interest in those kinds of questions as well.
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Dr. Selina Luger
I'd like to thank Dr. Pearl and Dr. Michaels for being here today and also our other authors of our spotlight series for contributing. And I invite you all to read these articles. I think they really do help us understand some of the challenges and provide us some guidelines on how to approach these patients, both with areas where we have made progress and areas where we need to make progress.
- [21:25]
Host
Thank you for listening to this review series on all. To read the articles, visit bloodjournal.org. this presentation is copyrighted by the American Society of Hematology.