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The Efficacy of Midostaurin in Subsets of AML

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute
Published: Wednesday, Dec 28, 2016


Transcript:

Richard M. Stone, MD:
AML is a heterogeneous disease, and even FLT3-mutant AML is heterogeneous. Certainly, the biggest type of heterogeneity is whether or not you have a FLT3 ITD mutation or a FLT3 TKD mutation, or point mutation, in the tyrosine kinase domain. And even if you have a FLT3 ITD mutation, there’s heterogeneity within that because somehow the high level of the FLT3 ITD allele, compared to the normal allele—that’s called the allelic ratio, and it’s been clear from studies that were done more than 10 years ago—those who have a high allelic burden of mutant disease do worse than those who have a lower burden of mutant allelic disease.

So, we stratified the trial to make sure we balanced the groups in both arms in terms of those who had a FLT3 TKD mutation, those who had a high allelic burden of FLT3 ITD, and those who had a low burden of FLT3 ITD. And the good news was the survival benefit of midostaurin was seen in all those three subgroups: TKD, high ITD, and low ITD. The issue of stem cell transplantation in FLT3 ITD and FLT3 TKD patients underwent some evolution over the course of the study. When we designed the study, we assumed that about 16% of patients would have allogeneic transplants in first remission because that’s what was going on in the United States, at least at the time the study was designed in the early part of the century.

However, over the course of time, data emerged that suggested if you have a FLT3 ITD mutation anyway—and maybe a FLT3 TKD mutation, but certainly a FLT3 ITD mutation—that you should have a stem cell transplant in first remission. The stem cell rate in first remission was 25%. The stem cell transplant rate for patients overall in the trial was 57%. So, obviously, a lot of patients got transplanted beyond first remission. But anyway, the transplant rate was a lot higher than we assumed it would be. I think, although we can’t prove definitively from this trial, that the overall pretty good results in the whole group were due to the fact that transplantation was commonly used.

Although it’s biased because I was the principal investigator of this trial, I think the significance is several fold. First, on a nonmedical or primarily medical issue, we show that an industrial government collaboration across continents was feasible because this trial was done mainly in Europe and in the United States, but also there were patients who went on in Australia and in South America. So, collaboration and collegiality were key to the success of this trial and may be necessary in a lot of different cancers that have relatively small subgroups based on our understanding of the disease biology based on genetics.

Of course, the biggest issue was that we think we improved the outcome for patients with this subtype of AML by adding a small molecule inhibitor to standard chemotherapy. So, in that regard, we accomplished our goa, and hopefully we can build on this by giving patients who have a FLT3 mutation a better outcome and build on it even further by adding other things that might make the results we saw in this trial even better.

Clearly, when the drug is approved, I would use it for the approved indication primarily. The approved indication at baseline will likely be for those with newly diagnosed AML who are between ages 18 and 59. If I had a patient who was between 60 and up who I was going to give chemotherapy to because they were fit and because they had a FLT3 mutation, which indicates a chemotherapy-responsive disease subset, I frankly would use midostaurin, if I could, even in the older adult who’s presenting with AML with a FLT3 mutation who is fit for chemotherapy. I don’t see any reason to suspect the benefit wouldn’t be there.

What about other subgroups? They need to be tested prospectively. But the ones that need to be tested are FLT3 wild-type patients. The drug, as I already mentioned, inhibits a lot of other enzymes that might be relevant in the pathophysiology of AML. Moreover, the drug in the RATIFY trial seemed to work even in those with a low allelic burden of ITD, implying that maybe it’s not only working through inhibition of FLT3. Finally, even wild-type patients may overexpress FLT3, and certainly midostaurin might have a use there. So, testing it in wild-type FLT3 patients of all ages will be important, but I would not use it in those patients until such time it’s proven to be beneficial in that subgroup. What about relapsed AML who haven’t yet seen a FLT3 inhibitor or haven’t yet seen midostaurin? I would consider it. It does have a role there. Other FLT3 inhibitors are being tested specifically in that context, and ideally, we’ll wait for the readout of those trials to see where they fit in the therapeutic armamentarium for this disease.

Another interesting topic is, should the drug be used after stem cell transplantation? That was not part of our trial, but there have been other trials that have used FLT3 inhibitors, either prophylactically after transplanting a FLT3-mutant patient or therapeutically if the patient relapses after transplant, where there’s been some suggestion of benefit of FLT3 inhibitors used in that situation. Moreover, there was a trial that was presented at ASH by the German AMLSG group that looked at using midostaurin before, during, and after transplant, and those results seemed to be good. I think the baseline use will be restricted to the type of patients and the schedules that we used in the RATIFY trial. But certainly, after transplantation, older adults and maybe even wild-type patients will be all grounds for further investigation.

Transcript Edited for Clarity
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Transcript:

Richard M. Stone, MD:
AML is a heterogeneous disease, and even FLT3-mutant AML is heterogeneous. Certainly, the biggest type of heterogeneity is whether or not you have a FLT3 ITD mutation or a FLT3 TKD mutation, or point mutation, in the tyrosine kinase domain. And even if you have a FLT3 ITD mutation, there’s heterogeneity within that because somehow the high level of the FLT3 ITD allele, compared to the normal allele—that’s called the allelic ratio, and it’s been clear from studies that were done more than 10 years ago—those who have a high allelic burden of mutant disease do worse than those who have a lower burden of mutant allelic disease.

So, we stratified the trial to make sure we balanced the groups in both arms in terms of those who had a FLT3 TKD mutation, those who had a high allelic burden of FLT3 ITD, and those who had a low burden of FLT3 ITD. And the good news was the survival benefit of midostaurin was seen in all those three subgroups: TKD, high ITD, and low ITD. The issue of stem cell transplantation in FLT3 ITD and FLT3 TKD patients underwent some evolution over the course of the study. When we designed the study, we assumed that about 16% of patients would have allogeneic transplants in first remission because that’s what was going on in the United States, at least at the time the study was designed in the early part of the century.

However, over the course of time, data emerged that suggested if you have a FLT3 ITD mutation anyway—and maybe a FLT3 TKD mutation, but certainly a FLT3 ITD mutation—that you should have a stem cell transplant in first remission. The stem cell rate in first remission was 25%. The stem cell transplant rate for patients overall in the trial was 57%. So, obviously, a lot of patients got transplanted beyond first remission. But anyway, the transplant rate was a lot higher than we assumed it would be. I think, although we can’t prove definitively from this trial, that the overall pretty good results in the whole group were due to the fact that transplantation was commonly used.

Although it’s biased because I was the principal investigator of this trial, I think the significance is several fold. First, on a nonmedical or primarily medical issue, we show that an industrial government collaboration across continents was feasible because this trial was done mainly in Europe and in the United States, but also there were patients who went on in Australia and in South America. So, collaboration and collegiality were key to the success of this trial and may be necessary in a lot of different cancers that have relatively small subgroups based on our understanding of the disease biology based on genetics.

Of course, the biggest issue was that we think we improved the outcome for patients with this subtype of AML by adding a small molecule inhibitor to standard chemotherapy. So, in that regard, we accomplished our goa, and hopefully we can build on this by giving patients who have a FLT3 mutation a better outcome and build on it even further by adding other things that might make the results we saw in this trial even better.

Clearly, when the drug is approved, I would use it for the approved indication primarily. The approved indication at baseline will likely be for those with newly diagnosed AML who are between ages 18 and 59. If I had a patient who was between 60 and up who I was going to give chemotherapy to because they were fit and because they had a FLT3 mutation, which indicates a chemotherapy-responsive disease subset, I frankly would use midostaurin, if I could, even in the older adult who’s presenting with AML with a FLT3 mutation who is fit for chemotherapy. I don’t see any reason to suspect the benefit wouldn’t be there.

What about other subgroups? They need to be tested prospectively. But the ones that need to be tested are FLT3 wild-type patients. The drug, as I already mentioned, inhibits a lot of other enzymes that might be relevant in the pathophysiology of AML. Moreover, the drug in the RATIFY trial seemed to work even in those with a low allelic burden of ITD, implying that maybe it’s not only working through inhibition of FLT3. Finally, even wild-type patients may overexpress FLT3, and certainly midostaurin might have a use there. So, testing it in wild-type FLT3 patients of all ages will be important, but I would not use it in those patients until such time it’s proven to be beneficial in that subgroup. What about relapsed AML who haven’t yet seen a FLT3 inhibitor or haven’t yet seen midostaurin? I would consider it. It does have a role there. Other FLT3 inhibitors are being tested specifically in that context, and ideally, we’ll wait for the readout of those trials to see where they fit in the therapeutic armamentarium for this disease.

Another interesting topic is, should the drug be used after stem cell transplantation? That was not part of our trial, but there have been other trials that have used FLT3 inhibitors, either prophylactically after transplanting a FLT3-mutant patient or therapeutically if the patient relapses after transplant, where there’s been some suggestion of benefit of FLT3 inhibitors used in that situation. Moreover, there was a trial that was presented at ASH by the German AMLSG group that looked at using midostaurin before, during, and after transplant, and those results seemed to be good. I think the baseline use will be restricted to the type of patients and the schedules that we used in the RATIFY trial. But certainly, after transplantation, older adults and maybe even wild-type patients will be all grounds for further investigation.

Transcript Edited for Clarity
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