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High-Dose Anthracycline Therapy in AML

Panelists: Naval G. Daver, MD, The University of Texas MD Anderson Cancer Center; Harry Erba, MD, PhD, Duke University; Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center; Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania; Raajit K. Rampal, MD, PhD Memorial Sloan Kettering Cancer Center
Published: Wednesday, Jan 16, 2019



Transcript: 

Harry Erba, MD, PhD: There might be benefits of intensifying chemotherapy in certain subsets. And there’s been a lot of talk about the intensification of the daunorubicin dose in patients with FLT3-mutated AML [acute myeloid leukemia]. Sasha, do you want to say a word about that?

Alexander Perl, MD: Well, there’s been 2 studies that have looked at this. There was a US study led by the niche group study, led by the Eastern Cooperative Oncology Group, the ECOG 1900 study that studied whether 45 mg/m2 or a higher dose of anthracycline at 90 mg/m2 administered in the first course of 7 and 3 therapy improved outcomes. And, importantly, on that study, anybody who needed a second cycle got the lower dose. So the total dose was never 2 rounds of 90 mg/m2. And that study showed that there was both a better CR rate and also a better overall survival for patients who got the higher dose of daunorubicin overall. And subsequent studies looked at long-term follow-up from those patients. And one of the groups that really seemed to benefit the most of this were patients with FLT3 ITD [internal tandem duplication] who had the substantially better overall survival, treated at the higher dose of daunorubicin, than those treated at the lower dose.

Now the problem with that approach is that 45 mg/m2 is not a dose that these days is commonly used in patients under the age of 60, which was everyone enrolled on that study. And 60 mg/m2 is a more commonly used dose at many centers. So you might ask the question, 60 and 90, are they the same? Are they different? Are they so similar that you can really just choose whatever works best there? And so in England, the NCRI [National Cancer Research Institute] actually did a study comparing 60 versus 90 as the first course. But what’s different here is that they gave 2 cycles to all patients, not 2 cycles if you needed a second based on an interim marrow. So we’re really looking at a cumulative anthracycline dose. It’s much higher on that study than really anything we looked at in the US. And that might be why they saw that there was no difference on that study between the 2 arms overall.

But then, interestingly, when they looked at a subset analysis after the study was done, they looked at the FLT3-mutated patients, and particularly those with FLT3 ITD, and saw even in that group that there was actually a survival benefit to the higher dose that was given on the first course. There really may be something there in terms of anthracycline sensitivity in FLT3 ITD–positive AML that suggests that we should be using higher doses of anthracycline, at least for daunorubicin in induction in these patients. Now, the real question in my mind now that we’re no longer just giving chemotherapy alone, we’re adding midostaurin or other FLT3 inhibitors for frontline therapy. Is there just an incremental improvement in outcome that you can get from a more intensive induction and you’ll get that with either a FLT3 inhibitor or a higher dose of daunorubicin? We don’t really know that. We don’t know that 90 mg/m2 plus midostaurin is better than 60. We do know it’s feasible. There were some data presented at the meeting that showed that it’s feasible to give daunorubicin at 90 mg/m2 and midostaurin, but we don’t actually know that that’s better.

Harry Erba, MD, PhD: In fact, there was a Korean study published in JCO [Journal of Clinical Oncology] looking at daunorubicin 90 mg/m2 for 3 days and idarubicin. Again, no difference except in the FLT3-mutated groups.

Mark J. Levis, MD, PhD: Although I would interject the cynic’s view of this. A lot of time and research energy are being spent in rearranging which anthracycline and which dose of cytarabine. I think we’ve pretty much maxed out the benefit we’re going to get from a cytotoxic backbone. I agree, you might tinker a bit with it, but moving ahead by incorporating targeted therapy, I suspect, is where we’re going to make good progress.

Harry Erba, MD, PhD: I completely agree, and that’s where we need to go. But the real question to you then is based on what Sasha said: Should the randomized phase III studies of these novel FLT3 inhibitors be done with a backbone of 90 mg/m2 with daunorubicin or does it not…

Mark J. Levis, MD, PhD: Having tried to do this worldwide, you will not get anybody to agree on a backbone. So you have to come up with this mishmash to satisfy everybody. You will never convince anybody in certain parts of the world that 90 is essential. There are those that think if you’re not giving idarubicin, you’re committing treason or you’re committing malpractice. I’m not kidding. So I don’t think the answer is there. I think the solution is it’s going to be this kind of general, most common regimen that resembles all of them together. I don’t think they’re going to settle on one as the winner.

Naval G. Daver, MD: One point I think is going to be when we add these new agents, and some of them are more potent—quizartinib, gilteritinib—especially in the cytopenia. I think that’s going to be more important. Do you have a room? And if 60 gives you more room, which it does—with 90 there is more prolonged myelosuppression—I would probably have the allowance to add the more potent FLT3 inhibitor, at least in trials, until we know more with the lower dose than maximize the dose. And that’s something we’re going to talk about.

Mark J. Levis, MD, PhD: I think that’s a great point.

Alexander Perl, MD: One thing that’s also important in that setting is just not all regimens are the same when you add in extra drugs. So one concern with 90 mg/m2 would be that there was more cardiotoxicity, which actually didn’t turn out to be the case at all. But when studies have looked at adding a FLT3 inhibitor to 7 and 3, you actually have to really pay attention to when you add that drug. Because if you overlap that drug with the anthracycline, you may actually affect the pharmacokinetics of the anthracycline, which could increase toxicity. So the RATIFY study used day 8 through day 21—and most of the studies going forward are using that same kind of design, where the FLT3 inhibitor and the anthracycline are not given at the same time. Important to remember if you ever need a second cycle of these drugs. You shouldn’t run them straight in.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: There might be benefits of intensifying chemotherapy in certain subsets. And there’s been a lot of talk about the intensification of the daunorubicin dose in patients with FLT3-mutated AML [acute myeloid leukemia]. Sasha, do you want to say a word about that?

Alexander Perl, MD: Well, there’s been 2 studies that have looked at this. There was a US study led by the niche group study, led by the Eastern Cooperative Oncology Group, the ECOG 1900 study that studied whether 45 mg/m2 or a higher dose of anthracycline at 90 mg/m2 administered in the first course of 7 and 3 therapy improved outcomes. And, importantly, on that study, anybody who needed a second cycle got the lower dose. So the total dose was never 2 rounds of 90 mg/m2. And that study showed that there was both a better CR rate and also a better overall survival for patients who got the higher dose of daunorubicin overall. And subsequent studies looked at long-term follow-up from those patients. And one of the groups that really seemed to benefit the most of this were patients with FLT3 ITD [internal tandem duplication] who had the substantially better overall survival, treated at the higher dose of daunorubicin, than those treated at the lower dose.

Now the problem with that approach is that 45 mg/m2 is not a dose that these days is commonly used in patients under the age of 60, which was everyone enrolled on that study. And 60 mg/m2 is a more commonly used dose at many centers. So you might ask the question, 60 and 90, are they the same? Are they different? Are they so similar that you can really just choose whatever works best there? And so in England, the NCRI [National Cancer Research Institute] actually did a study comparing 60 versus 90 as the first course. But what’s different here is that they gave 2 cycles to all patients, not 2 cycles if you needed a second based on an interim marrow. So we’re really looking at a cumulative anthracycline dose. It’s much higher on that study than really anything we looked at in the US. And that might be why they saw that there was no difference on that study between the 2 arms overall.

But then, interestingly, when they looked at a subset analysis after the study was done, they looked at the FLT3-mutated patients, and particularly those with FLT3 ITD, and saw even in that group that there was actually a survival benefit to the higher dose that was given on the first course. There really may be something there in terms of anthracycline sensitivity in FLT3 ITD–positive AML that suggests that we should be using higher doses of anthracycline, at least for daunorubicin in induction in these patients. Now, the real question in my mind now that we’re no longer just giving chemotherapy alone, we’re adding midostaurin or other FLT3 inhibitors for frontline therapy. Is there just an incremental improvement in outcome that you can get from a more intensive induction and you’ll get that with either a FLT3 inhibitor or a higher dose of daunorubicin? We don’t really know that. We don’t know that 90 mg/m2 plus midostaurin is better than 60. We do know it’s feasible. There were some data presented at the meeting that showed that it’s feasible to give daunorubicin at 90 mg/m2 and midostaurin, but we don’t actually know that that’s better.

Harry Erba, MD, PhD: In fact, there was a Korean study published in JCO [Journal of Clinical Oncology] looking at daunorubicin 90 mg/m2 for 3 days and idarubicin. Again, no difference except in the FLT3-mutated groups.

Mark J. Levis, MD, PhD: Although I would interject the cynic’s view of this. A lot of time and research energy are being spent in rearranging which anthracycline and which dose of cytarabine. I think we’ve pretty much maxed out the benefit we’re going to get from a cytotoxic backbone. I agree, you might tinker a bit with it, but moving ahead by incorporating targeted therapy, I suspect, is where we’re going to make good progress.

Harry Erba, MD, PhD: I completely agree, and that’s where we need to go. But the real question to you then is based on what Sasha said: Should the randomized phase III studies of these novel FLT3 inhibitors be done with a backbone of 90 mg/m2 with daunorubicin or does it not…

Mark J. Levis, MD, PhD: Having tried to do this worldwide, you will not get anybody to agree on a backbone. So you have to come up with this mishmash to satisfy everybody. You will never convince anybody in certain parts of the world that 90 is essential. There are those that think if you’re not giving idarubicin, you’re committing treason or you’re committing malpractice. I’m not kidding. So I don’t think the answer is there. I think the solution is it’s going to be this kind of general, most common regimen that resembles all of them together. I don’t think they’re going to settle on one as the winner.

Naval G. Daver, MD: One point I think is going to be when we add these new agents, and some of them are more potent—quizartinib, gilteritinib—especially in the cytopenia. I think that’s going to be more important. Do you have a room? And if 60 gives you more room, which it does—with 90 there is more prolonged myelosuppression—I would probably have the allowance to add the more potent FLT3 inhibitor, at least in trials, until we know more with the lower dose than maximize the dose. And that’s something we’re going to talk about.

Mark J. Levis, MD, PhD: I think that’s a great point.

Alexander Perl, MD: One thing that’s also important in that setting is just not all regimens are the same when you add in extra drugs. So one concern with 90 mg/m2 would be that there was more cardiotoxicity, which actually didn’t turn out to be the case at all. But when studies have looked at adding a FLT3 inhibitor to 7 and 3, you actually have to really pay attention to when you add that drug. Because if you overlap that drug with the anthracycline, you may actually affect the pharmacokinetics of the anthracycline, which could increase toxicity. So the RATIFY study used day 8 through day 21—and most of the studies going forward are using that same kind of design, where the FLT3 inhibitor and the anthracycline are not given at the same time. Important to remember if you ever need a second cycle of these drugs. You shouldn’t run them straight in.

Transcript Edited for Clarity 
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