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Updates on Chemotherapy Regimens 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: Thursday, Jan 10, 2019



Transcript: 

Harry Erba, MD, PhD: Well, we haven’t solved that. We’re going to continue to wonder about that. In this era of targeted therapy, I don’t know if we’ve solved the backbone of chemotherapy yet either. And there have been a number of interesting abstracts presented at ASH [American Society of Hematology] this year regarding what is the best chemotherapy regimen for our patients. Naval, do you want to start?

Naval G. Daver, MD: Yeah, sure. I think that’s a big point of discussion that’s been going on for a couple of decades now: what is the idea of backbone induction chemotherapy. And at MD Anderson our preference has been a purine analog with a cytarabine/anthracycline-based regimen very similar to the British regimen that Alan Burnett has used for many years, as well as now the Polish group. And at this year’s ASH annual meeting, there were 2 abstracts. One was from our group by Dr. Alfayez, one of our fellows who presented the updated results of CLIA2, which is cladribine/idarubicin/cytarabine modeled over the phase III positive data, which the Polish group used with cladribine with 3+7.

So what was shown is that the response rates, which I really think are a difficult thing to use in induction, were pretty much comparable to what you would get with most induction regimens. I think what we’re seeing is that the tolerability—which was one of the big concerns for many people to apply the British or the Polish data, at least in a big center—was very similar to what we would expect with 3+7. I think the early mortality, if I recall, was 5% or less, which is very acceptable. We didn’t have very significant prolonged cytopenia. So we think that, safety wise, this is a good regimen. We believe that the Polish data, that this was superior.

Now, there’s a second phase III, I understand, ongoing in Europe which may or may not answer the question at this time. So that was our data. And we’re continuing to use this as a backbone, moreso now because what’s becoming more important, in my mind really, than the backbone regimen per se is what you add to it. So, if you have a FLT3 mutation, we’re actually adding sorafenib or midostaurin. In the future, we will have a study, in fact, looking maybe with adding quizartinib to that. And I think these will make more of the long-term survival impact than the dose of daunorubicin, idarubicin.

The other abstract that was presented was an interesting experience that I had not known about until we saw some of the data at ASH. It’s a community university setting. I think this is a group out of Atlanta where they looked at their outcomes of induction. They basically modeled what Alan Burnett and MRC15 had published, which was the FLAG-Ida [fludarabine/high-dose cytarabine (ara-C)/granulocyte colony-stimulating factor] followed by induction followed by ADE [cytarabine/daunorubicin/etoposide] induction consolidation. And they compared these outcomes to a 3+7–like regimen, showing that the response rates were higher with the FLAG-Ida and the survival also seemed to be higher. So their conclusion was that that’s what they were using. They feel that the British regimen seemed to be more effective.

I think the key with a lot of these is it’s where you do this. I think if you have leukemia expertise, centers that have a lot of support, infectious disease backup, or the British group, which does everything in a large institution setting, I think you can do these purine analog-based combinations. They seem to be superior. The Polish data showed a phase III. And, in fact, in Alan Burnett’s MRC15, the FLAG-Ida was also superior to the 3+7 backbone. But I think the same thing: It’s very hard to translate into general community practice where you have maybe 5 or 8 or 10 leukemias a year. And there is more myelosuppression. Even though it may not be very much higher, it’s there. There is more concern for infection. So I think I would recommend doing these in larger academic settings, and that’s where most AML [acute myeloid leukemia] should be treated anyways.

Harry Erba, MD, PhD: Regarding that single-center analysis of IDA-FLAG versus 7 and 3, they showed actually almost identical CR rates with 7 and 3 and FLAG-Ida. They were virtually identical. Three-quarters of those patients went on to allotransplant. These were patients with intermediate- and poor-risk cytogenetics. But what was interesting in the abstract was that the survival post transplant was superior in those patients who got FLAG-Ida compared to 7 and 3, of course trying to lead you to the conclusion that there is something about the remission that led to a better outcome, maybe a better depth.

Naval G. Daver, MD: MRD [minimal residual disease].

Harry Erba, MD, PhD: MRD, depth of remission. Of course, there are no data on that. My biggest concern about those kind of retrospective analyses is that the doctor seeing the patient in some way made a decision between giving 7 and 3 and giving what arguably is a more intensive regimen, more prolonged myelosuppression, higher doses of ara-C. And so because of that, in this kind of setting, we really can’t make any conclusions about which chemotherapy regimen is superior. Unfortunately, the SWOG 1203 study didn’t show a difference between 7 and 3 and IDA with high-dose ara-C. So it has to do with patient selection at the hospital. But in a randomized trial, we haven’t been able to show any difference.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: Well, we haven’t solved that. We’re going to continue to wonder about that. In this era of targeted therapy, I don’t know if we’ve solved the backbone of chemotherapy yet either. And there have been a number of interesting abstracts presented at ASH [American Society of Hematology] this year regarding what is the best chemotherapy regimen for our patients. Naval, do you want to start?

Naval G. Daver, MD: Yeah, sure. I think that’s a big point of discussion that’s been going on for a couple of decades now: what is the idea of backbone induction chemotherapy. And at MD Anderson our preference has been a purine analog with a cytarabine/anthracycline-based regimen very similar to the British regimen that Alan Burnett has used for many years, as well as now the Polish group. And at this year’s ASH annual meeting, there were 2 abstracts. One was from our group by Dr. Alfayez, one of our fellows who presented the updated results of CLIA2, which is cladribine/idarubicin/cytarabine modeled over the phase III positive data, which the Polish group used with cladribine with 3+7.

So what was shown is that the response rates, which I really think are a difficult thing to use in induction, were pretty much comparable to what you would get with most induction regimens. I think what we’re seeing is that the tolerability—which was one of the big concerns for many people to apply the British or the Polish data, at least in a big center—was very similar to what we would expect with 3+7. I think the early mortality, if I recall, was 5% or less, which is very acceptable. We didn’t have very significant prolonged cytopenia. So we think that, safety wise, this is a good regimen. We believe that the Polish data, that this was superior.

Now, there’s a second phase III, I understand, ongoing in Europe which may or may not answer the question at this time. So that was our data. And we’re continuing to use this as a backbone, moreso now because what’s becoming more important, in my mind really, than the backbone regimen per se is what you add to it. So, if you have a FLT3 mutation, we’re actually adding sorafenib or midostaurin. In the future, we will have a study, in fact, looking maybe with adding quizartinib to that. And I think these will make more of the long-term survival impact than the dose of daunorubicin, idarubicin.

The other abstract that was presented was an interesting experience that I had not known about until we saw some of the data at ASH. It’s a community university setting. I think this is a group out of Atlanta where they looked at their outcomes of induction. They basically modeled what Alan Burnett and MRC15 had published, which was the FLAG-Ida [fludarabine/high-dose cytarabine (ara-C)/granulocyte colony-stimulating factor] followed by induction followed by ADE [cytarabine/daunorubicin/etoposide] induction consolidation. And they compared these outcomes to a 3+7–like regimen, showing that the response rates were higher with the FLAG-Ida and the survival also seemed to be higher. So their conclusion was that that’s what they were using. They feel that the British regimen seemed to be more effective.

I think the key with a lot of these is it’s where you do this. I think if you have leukemia expertise, centers that have a lot of support, infectious disease backup, or the British group, which does everything in a large institution setting, I think you can do these purine analog-based combinations. They seem to be superior. The Polish data showed a phase III. And, in fact, in Alan Burnett’s MRC15, the FLAG-Ida was also superior to the 3+7 backbone. But I think the same thing: It’s very hard to translate into general community practice where you have maybe 5 or 8 or 10 leukemias a year. And there is more myelosuppression. Even though it may not be very much higher, it’s there. There is more concern for infection. So I think I would recommend doing these in larger academic settings, and that’s where most AML [acute myeloid leukemia] should be treated anyways.

Harry Erba, MD, PhD: Regarding that single-center analysis of IDA-FLAG versus 7 and 3, they showed actually almost identical CR rates with 7 and 3 and FLAG-Ida. They were virtually identical. Three-quarters of those patients went on to allotransplant. These were patients with intermediate- and poor-risk cytogenetics. But what was interesting in the abstract was that the survival post transplant was superior in those patients who got FLAG-Ida compared to 7 and 3, of course trying to lead you to the conclusion that there is something about the remission that led to a better outcome, maybe a better depth.

Naval G. Daver, MD: MRD [minimal residual disease].

Harry Erba, MD, PhD: MRD, depth of remission. Of course, there are no data on that. My biggest concern about those kind of retrospective analyses is that the doctor seeing the patient in some way made a decision between giving 7 and 3 and giving what arguably is a more intensive regimen, more prolonged myelosuppression, higher doses of ara-C. And so because of that, in this kind of setting, we really can’t make any conclusions about which chemotherapy regimen is superior. Unfortunately, the SWOG 1203 study didn’t show a difference between 7 and 3 and IDA with high-dose ara-C. So it has to do with patient selection at the hospital. But in a randomized trial, we haven’t been able to show any difference.

Transcript Edited for Clarity 
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