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Post Remission Decisions in AML

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute
Published: Friday, Dec 09, 2016


Transcript:

Richard M. Stone, MD:
One of the biggest questions we have in AML treatment is how best to consolidate patients who’ve achieved remission with initial induction therapy, whether that induction therapy is with standard 3+7 or, perhaps for an older patient, with a hypomethylating agent. The purpose of consolidation therapy, in general, is to clear the undetectable blasts so that the patient can be cured. What’s the best way to do that? I would submit that for the average non-older patient with AML, allogeneic transplant is going to be the way to go. There’s a relatively smaller subset of patients who can “get away” with not having to go through the rigors and risk of a transplant. The patients, in whom I definitively would not think of allogeneic transplanting in first remission, are those with core- binding factor cytogenetic abnormalities, inv(16) and t(8;21), with the exception that those who have a c-KIT mutation do worse and maybe they should be transplanted. The only group of patients with normal cytogenetics, in whom I would not consider transplanting in first remission, are those with an FLT3 ITD wild-type status, and who also have an NPM1 mutation. This also is a bit controversial because it depends on the minimal residual disease status at remission. Again, that harkens back to the controversy of the use of minimal residual disease. To make a long story short, if a patient has either a match sibling donor or a good unrelated adult match, I favor transplant, except in those patients who have c-KIT wild-type, t(8;21) and inv(16) cytogenetics, and in those normal chromosome patients who have NPM1 mutations, but don’t have an FLT3 ITD mutation.

Hervé Dombret, MD: Once you achieve complete remission in your patient, the problem is how to prevent relapse of the disease because relapses are very, very frequent. Roughly, the complete remission rate, depending of the patient population, is above 75%. So, once you get a complete remission, the problem is to prevent relapse. You can do that by several techniques or treatments. The first is to continue intensive chemotherapy. The second is to propose hematopoietic stem cell transplantation. There is autologous stem cell transplantation that has been done in the previous years, but mostly there is allogeneic stem cell transplantation when you can identify a donor of stem cell for your patient in particular. This is a big decision after complete remission achievement—which patients should be transplanted and which should not? And this is based now on genomic analyses.

So, genomic mutational status allowed us to define favorable-risk AML as opposed to what we called intermediate-risk AML or unfavorable-risk AML. This is based on mutations, and only patients with intermediate- or unfavorable-risk are candidates for stem cell transplantation in first remission. Because for the patients with favorable-risk AML, the relapse rate is not so high and you cannot propose allogeneic stem cell transplantation, which is associated with a transplant-related mortality to the patient with a relatively low risk of relapse. Most of the groups and the doctors agree with this way of proposing transplantation in your patients.

When you need to give consolidation chemotherapy after remission achievement, there is really no standardized way to do that. What is known is that intensification of the dose have been beneficial to the patients. But, the number of courses you have to give to a patient after remission achievement, and the exact composition of these courses in term of drugs and dosage, are not standardized. What we are using in my country, in France, is very, very simple. It is based on 3 courses of high-dose cytarabine, one single drug, cytarabine, at high dose given during 3 courses.

Transcript Edited for Clarity
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Transcript:

Richard M. Stone, MD:
One of the biggest questions we have in AML treatment is how best to consolidate patients who’ve achieved remission with initial induction therapy, whether that induction therapy is with standard 3+7 or, perhaps for an older patient, with a hypomethylating agent. The purpose of consolidation therapy, in general, is to clear the undetectable blasts so that the patient can be cured. What’s the best way to do that? I would submit that for the average non-older patient with AML, allogeneic transplant is going to be the way to go. There’s a relatively smaller subset of patients who can “get away” with not having to go through the rigors and risk of a transplant. The patients, in whom I definitively would not think of allogeneic transplanting in first remission, are those with core- binding factor cytogenetic abnormalities, inv(16) and t(8;21), with the exception that those who have a c-KIT mutation do worse and maybe they should be transplanted. The only group of patients with normal cytogenetics, in whom I would not consider transplanting in first remission, are those with an FLT3 ITD wild-type status, and who also have an NPM1 mutation. This also is a bit controversial because it depends on the minimal residual disease status at remission. Again, that harkens back to the controversy of the use of minimal residual disease. To make a long story short, if a patient has either a match sibling donor or a good unrelated adult match, I favor transplant, except in those patients who have c-KIT wild-type, t(8;21) and inv(16) cytogenetics, and in those normal chromosome patients who have NPM1 mutations, but don’t have an FLT3 ITD mutation.

Hervé Dombret, MD: Once you achieve complete remission in your patient, the problem is how to prevent relapse of the disease because relapses are very, very frequent. Roughly, the complete remission rate, depending of the patient population, is above 75%. So, once you get a complete remission, the problem is to prevent relapse. You can do that by several techniques or treatments. The first is to continue intensive chemotherapy. The second is to propose hematopoietic stem cell transplantation. There is autologous stem cell transplantation that has been done in the previous years, but mostly there is allogeneic stem cell transplantation when you can identify a donor of stem cell for your patient in particular. This is a big decision after complete remission achievement—which patients should be transplanted and which should not? And this is based now on genomic analyses.

So, genomic mutational status allowed us to define favorable-risk AML as opposed to what we called intermediate-risk AML or unfavorable-risk AML. This is based on mutations, and only patients with intermediate- or unfavorable-risk are candidates for stem cell transplantation in first remission. Because for the patients with favorable-risk AML, the relapse rate is not so high and you cannot propose allogeneic stem cell transplantation, which is associated with a transplant-related mortality to the patient with a relatively low risk of relapse. Most of the groups and the doctors agree with this way of proposing transplantation in your patients.

When you need to give consolidation chemotherapy after remission achievement, there is really no standardized way to do that. What is known is that intensification of the dose have been beneficial to the patients. But, the number of courses you have to give to a patient after remission achievement, and the exact composition of these courses in term of drugs and dosage, are not standardized. What we are using in my country, in France, is very, very simple. It is based on 3 courses of high-dose cytarabine, one single drug, cytarabine, at high dose given during 3 courses.

Transcript Edited for Clarity
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