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Therapeutic Approaches Based on Mutations in AML

Panelists: Harry Erba, MD, PhD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, MS, Hospital of The University of Pennsylvania; Daniel Pollyea, MD, MS, University of Colorado, Anschutz Medical Campus; Eunice Wang, MD, Roswell Park Comprehensive Cancer Center
Published: Monday, Jul 29, 2019



Transcript: 

Harry Erba, MD, PhD: We’ve also mentioned PCR [polymerase chain reaction] for IDH1/2, and the prognostic implications of those aren’t quite as clear. Clearly, a therapeutic implication, but even in the previously untreated patient? Dan, what do you think?

Daniel Pollyea, MD, MS: I think there’s some emerging role for the use of an IDH inhibitor in the previously untreated setting. There’s the recent approval by the FDA for ivosidenib for that purpose. So it’s an option and one that can be explored. And when we’re thinking about what testing needs to be done in what timeframe that would be relevant for our patients, I think that does rise to that level now because there is a targeted therapy that has an approved role there.

It’s not quite the same as FLT3 where there’s a treatment decision that needs to be made for the upfront treatment of an induction chemotherapy-eligible patient at the moment. But we’ll see. There are some exciting clinical trials that are working on that question as to whether an IDH inhibitor in the upfront setting for a chemotherapy-eligible patient might some day have some benefit. So I think it’s totally appropriate to try to get access to that knowledge in the early days after diagnosis of a patient if that’s something that’s on the radar.

Harry Erba, MD, PhD: I think with the changes or the recent approvals, 8 new therapies for our patients with AML [acute myeloid leukemia] in the last couple of years, there’s been a change in our message that I think we should be giving about these molecular cytogenetic tests at the time of diagnosis. In the past, these were purely for prognostication and mostly to help determine which patients may not need to undergo allogeneic transplant in first remission, the core binding factor leukemias, NPM-mutated, CEBPA-mutated. But things have completely changed, and we are actually making treatment decisions every day, at least at our place, I assume at yours as well, based on these results: core binding factors, maybe gemtuzumab; poor-risk cytogenetics in an apparently de novo patient, maybe liposomal daunorubicin/cytarabine; and of course targeting FLT3 and targeting IDH. So clearly, this is important information not just for prognostication but how are you actually going to treat the next AML patient.

Eunice Wang, MD: Given the pace of these new agents and the rapid approval over the last 2 years, I think it’s essential that that information you just gave us be communicated to all of the individuals who  are involved in making the diagnosis of AML at your center, specifically the hematopathologist, the flow cytometry people, the cytogeneticists because I think in the past there was no urgency. A lot of times they think that we’re just asking them for that information because we’re impatient and we want it for a clinical trial. I think that because they’re not tied into treatment of the patient, they may not realize that you are actually waiting for them to [provide the] result. So it becomes the next task that they have to take care of, and they don’t recognize that it is affecting individuals and outcomes in our patients.

Harry Erba, MD, PhD: I agree with that. I got to Duke [University] a year ago, and it was eye-opening to me to actually meet with our cytogenetics people and say the reason why I need you to change practices on a FISH [fluorescence in situ hybridization] panel is that this is what I’m going to do in each of these situations. And they were really happy to have that dialogue.

Eunice Wang, MD: They didn’t know that.

Harry Erba, MD, PhD: They didn’t know that, and then we worked through a process of making sure that they don’t have to expedite every single FISH panel. We figured out how to tell them what’s the most important. So it clearly needs a dialogue at your centers.

Daniel Pollyea, MD, MS: I think that’s the key because we clinical leukemia doctors have to decide what do we need and what do we want. And there are differences and we’re working among a big team with limited resources. But like Harry said, when you actually plot out what is going to change what you do in the immediate term, I think all of our colleagues are always very agreeable to help with that aspect of patient care, at least that’s what I’ve found.

Alexander E. Perl, MD, MS: I think if you’re going to make a hierarchy, the things you need to know really fast are, is this APL [acute promyleocytic leukemia]? If there’s any morphologic, flow, or clinical suspicion of it, that’s the first thing you need to know, obviously once you know this is myeloid leukemia. Core binding factor for us is the next thing we want to know because that would drive a choice of using gemtuzumab in front-line, intensive chemotherapy. Once you find out, for example, a patient doesn’t have those 2 groups of genetic lesions, really the question for us is are we going to use liposomal daunorubicin/Ara-C, CPX-351. And if the patient is somebody who we think would benefit from that, we’re doing the very same kind of FISH panel approach to say whether we would ultimately get a karyotype that would suggest myelodysplasia-related leukemia. If we have all that information back, we’re ready to start.

At least in my institution, that’s all that we need in our hands to say we know this patient would benefit from intensive chemotherapy, let’s start 7+3 [cytarabine/daunorubicin]. And then we’ve sent off the other data in terms of additional prognostic information, which when it comes back, we can add an additional agent. If the patient has an IDH mutation and we would want to add an IDH inhibitor, again there’s not data presently showing superiority for that, but there are data showing superiority for adding midostaurin, and that’s basically our jump-off point for there. So that’s the information we would send off and the algorithm we would use.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: We’ve also mentioned PCR [polymerase chain reaction] for IDH1/2, and the prognostic implications of those aren’t quite as clear. Clearly, a therapeutic implication, but even in the previously untreated patient? Dan, what do you think?

Daniel Pollyea, MD, MS: I think there’s some emerging role for the use of an IDH inhibitor in the previously untreated setting. There’s the recent approval by the FDA for ivosidenib for that purpose. So it’s an option and one that can be explored. And when we’re thinking about what testing needs to be done in what timeframe that would be relevant for our patients, I think that does rise to that level now because there is a targeted therapy that has an approved role there.

It’s not quite the same as FLT3 where there’s a treatment decision that needs to be made for the upfront treatment of an induction chemotherapy-eligible patient at the moment. But we’ll see. There are some exciting clinical trials that are working on that question as to whether an IDH inhibitor in the upfront setting for a chemotherapy-eligible patient might some day have some benefit. So I think it’s totally appropriate to try to get access to that knowledge in the early days after diagnosis of a patient if that’s something that’s on the radar.

Harry Erba, MD, PhD: I think with the changes or the recent approvals, 8 new therapies for our patients with AML [acute myeloid leukemia] in the last couple of years, there’s been a change in our message that I think we should be giving about these molecular cytogenetic tests at the time of diagnosis. In the past, these were purely for prognostication and mostly to help determine which patients may not need to undergo allogeneic transplant in first remission, the core binding factor leukemias, NPM-mutated, CEBPA-mutated. But things have completely changed, and we are actually making treatment decisions every day, at least at our place, I assume at yours as well, based on these results: core binding factors, maybe gemtuzumab; poor-risk cytogenetics in an apparently de novo patient, maybe liposomal daunorubicin/cytarabine; and of course targeting FLT3 and targeting IDH. So clearly, this is important information not just for prognostication but how are you actually going to treat the next AML patient.

Eunice Wang, MD: Given the pace of these new agents and the rapid approval over the last 2 years, I think it’s essential that that information you just gave us be communicated to all of the individuals who  are involved in making the diagnosis of AML at your center, specifically the hematopathologist, the flow cytometry people, the cytogeneticists because I think in the past there was no urgency. A lot of times they think that we’re just asking them for that information because we’re impatient and we want it for a clinical trial. I think that because they’re not tied into treatment of the patient, they may not realize that you are actually waiting for them to [provide the] result. So it becomes the next task that they have to take care of, and they don’t recognize that it is affecting individuals and outcomes in our patients.

Harry Erba, MD, PhD: I agree with that. I got to Duke [University] a year ago, and it was eye-opening to me to actually meet with our cytogenetics people and say the reason why I need you to change practices on a FISH [fluorescence in situ hybridization] panel is that this is what I’m going to do in each of these situations. And they were really happy to have that dialogue.

Eunice Wang, MD: They didn’t know that.

Harry Erba, MD, PhD: They didn’t know that, and then we worked through a process of making sure that they don’t have to expedite every single FISH panel. We figured out how to tell them what’s the most important. So it clearly needs a dialogue at your centers.

Daniel Pollyea, MD, MS: I think that’s the key because we clinical leukemia doctors have to decide what do we need and what do we want. And there are differences and we’re working among a big team with limited resources. But like Harry said, when you actually plot out what is going to change what you do in the immediate term, I think all of our colleagues are always very agreeable to help with that aspect of patient care, at least that’s what I’ve found.

Alexander E. Perl, MD, MS: I think if you’re going to make a hierarchy, the things you need to know really fast are, is this APL [acute promyleocytic leukemia]? If there’s any morphologic, flow, or clinical suspicion of it, that’s the first thing you need to know, obviously once you know this is myeloid leukemia. Core binding factor for us is the next thing we want to know because that would drive a choice of using gemtuzumab in front-line, intensive chemotherapy. Once you find out, for example, a patient doesn’t have those 2 groups of genetic lesions, really the question for us is are we going to use liposomal daunorubicin/Ara-C, CPX-351. And if the patient is somebody who we think would benefit from that, we’re doing the very same kind of FISH panel approach to say whether we would ultimately get a karyotype that would suggest myelodysplasia-related leukemia. If we have all that information back, we’re ready to start.

At least in my institution, that’s all that we need in our hands to say we know this patient would benefit from intensive chemotherapy, let’s start 7+3 [cytarabine/daunorubicin]. And then we’ve sent off the other data in terms of additional prognostic information, which when it comes back, we can add an additional agent. If the patient has an IDH mutation and we would want to add an IDH inhibitor, again there’s not data presently showing superiority for that, but there are data showing superiority for adding midostaurin, and that’s basically our jump-off point for there. So that’s the information we would send off and the algorithm we would use.

Transcript Edited for Clarity
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