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Acute Myeloid Leukemia: Understanding Biologic Drivers

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Friday, Jan 19, 2018



Transcript: 

Harry Erba, MD, PhD: Hello, and thank you for joining this OncLive® Peer Exchange® titled “The Era of Targeted Therapy for Acute Myeloid Leukemia.” In recent years, we have made considerable progress in learning about the pathogenesis of acute myeloid leukemia, leading to the very recent FDA approval of several novel targeted therapies with more on the way. In this OncLive® Peer Exchange® discussion, we will discuss the incorporation of new treatment options into clinical care, the promise of minimal residual disease testing in the optimal management of acute myeloid leukemia, and emerging strategies for improving patient outcomes. We’ll review the data from the ASH 2017 Annual Meeting and how the newest research will impact the way we treat our patients.

I am Dr. Harry Erba, and I am the chair of the SWOG Leukemia Committee and professor of internal medicine at the University of Alabama in Birmingham. Participating today on our distinguished panel are Dr. Jorge Cortes, chief of the CML and AML sections and deputy chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Sasha Perl, associate professor of medicine in the Leukemia Program of the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia; and Dr. Eunice Wang, chief of the Leukemia Service and professor of oncology in the Department of Medicine at the Roswell Park Cancer Institute in Buffalo, New York. Thank you so much for joining us, and let’s begin.

In recent years, with the development of next-generation sequencing that is more rapid and less costly, we have learned a lot about the molecular drivers of acute myeloid leukemia. Sasha, can you bring us up to date on that subject?

Alexander E. Perl, MD: I think there has been a nice summary of this published by Papaemmanuil and colleagues from Memorial Sloan Kettering looking at the genetics of AML and really expanding upon the huge effort done by the TCGA, The Cancer Genome Atlas project. What Dr. Papaemmanuil did was basically a sequencing of over 1500 patients treated on German cooperative group studies looking to categorize the molecular lesions found into functionally important, and hopefully not overlapping, categorizations that you could use to define patient groups and prognostic information. If you found it, basically you could segregate patients based on a number of factors. There are 3 that really emerged, 2 of which we can look at karyotype and 1 that comes from gene sequence mutations.

The first are patients who have gene fusions, and these are things that we know. We can think of APL as being AML with a translocation between chromosome 15 and 17. So, these are current genetic aberrations that we have already defined. But she was able to break that out into recurrent gene fusions. The next group were patients who had aneuploidy, which was often seen in the presence of TP53 mutations. These patients had chromosomal abnormalities, but these are the patients who we treat who have often very complex karyotypes. You could get a cytogenetics report back, and it would be a whole page of abnormalities: deletions, mitosomes, things like that. And the last patients were generally patients with very few cytogenetic abnormalities, but often a number of gene sequence mutations that were highly recurrent. So in this study, there were over 150 targeted gene sequences that they looked at and they found mutations in the majority of those genes, but each patient would only have maybe 3, 4, or 5 mutations in their leukemia present at diagnosis.

Looking at the patterns here, they were able to segregate patients into defining features even within this, and some of those were mutations that we’re very familiar with—nucleophosmin being one, CEBP alpha double mutations being another. There’s another group that has mutations that alter either the spliceosome complex or the chromatin remodeling. So, there’s a group of patients who have different functional mutations, but very similar prognostic grouping. From this, you could basically define, I believe, 11 different categories of patients based on where they fell in that; whether they had recurrent gene fusions in the specific lesion, the presence or absence to aneuploidy being a defining lesion. And then, if they had gene sequence mutations, where they fell there was highly prognostic to how patients did.
This is a huge and very complicated study. It really is interesting, because if you look at the patients, especially in the third group of a gene sequence mutation, it goes way beyond what we currently have for prognostic models. It can look at not only 1 gene mutation that’s prognostic, but also at combinations of 2 at a time or 3 at a time to say how patients will do. That goes beyond our current prognostic categorization, either by the NCCN or the ELN guidelines. I think that is notable, because it’s those combinations not of just 1 gene, but several genes together, that really tell us how that group is going to do.

Harry Erba, MD, PhD: What I thought was interesting about that analysis was that some of the data were quite consistent with data coming from other studies. For example, the group of patients who she identified from that study with mutations in the genes for spliceosome enzymes and chromatin modifiers—that same group of enzymes, or gene mutations, have also been identified as being more specific for secondary acute myeloid leukemia based on data published by Coleman Lindsley from a prior study of secondary acute myeloid leukemia.
The other thing is when we look at clonal hematopoiesis of indeterminate prognosis, those are the same classes of mutations that are occurring and may underlie some of the explanation of why our older patients who finally develop acute myeloid leukemia are doing so poorly.

Alexander E. Perl, MD: Yes, certainly, if you look at the gambit of who winds up with which lesion, older patients are much more likely to wind up with that third group that’s defined by its specific gene mutations, and often that arises out of clonal hematopoiesis of indeterminate potential, or CHIP. Or, they’re patients with aneuploidy and p53 mutations. And yes, you can see secondary leukemias, or secondary myeloid neoplasms, with either of those 2 groups. You can actually see them with the gene fusions as well, often after topoisomerase II poisons or anthracyclines.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: Hello, and thank you for joining this OncLive® Peer Exchange® titled “The Era of Targeted Therapy for Acute Myeloid Leukemia.” In recent years, we have made considerable progress in learning about the pathogenesis of acute myeloid leukemia, leading to the very recent FDA approval of several novel targeted therapies with more on the way. In this OncLive® Peer Exchange® discussion, we will discuss the incorporation of new treatment options into clinical care, the promise of minimal residual disease testing in the optimal management of acute myeloid leukemia, and emerging strategies for improving patient outcomes. We’ll review the data from the ASH 2017 Annual Meeting and how the newest research will impact the way we treat our patients.

I am Dr. Harry Erba, and I am the chair of the SWOG Leukemia Committee and professor of internal medicine at the University of Alabama in Birmingham. Participating today on our distinguished panel are Dr. Jorge Cortes, chief of the CML and AML sections and deputy chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Sasha Perl, associate professor of medicine in the Leukemia Program of the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia; and Dr. Eunice Wang, chief of the Leukemia Service and professor of oncology in the Department of Medicine at the Roswell Park Cancer Institute in Buffalo, New York. Thank you so much for joining us, and let’s begin.

In recent years, with the development of next-generation sequencing that is more rapid and less costly, we have learned a lot about the molecular drivers of acute myeloid leukemia. Sasha, can you bring us up to date on that subject?

Alexander E. Perl, MD: I think there has been a nice summary of this published by Papaemmanuil and colleagues from Memorial Sloan Kettering looking at the genetics of AML and really expanding upon the huge effort done by the TCGA, The Cancer Genome Atlas project. What Dr. Papaemmanuil did was basically a sequencing of over 1500 patients treated on German cooperative group studies looking to categorize the molecular lesions found into functionally important, and hopefully not overlapping, categorizations that you could use to define patient groups and prognostic information. If you found it, basically you could segregate patients based on a number of factors. There are 3 that really emerged, 2 of which we can look at karyotype and 1 that comes from gene sequence mutations.

The first are patients who have gene fusions, and these are things that we know. We can think of APL as being AML with a translocation between chromosome 15 and 17. So, these are current genetic aberrations that we have already defined. But she was able to break that out into recurrent gene fusions. The next group were patients who had aneuploidy, which was often seen in the presence of TP53 mutations. These patients had chromosomal abnormalities, but these are the patients who we treat who have often very complex karyotypes. You could get a cytogenetics report back, and it would be a whole page of abnormalities: deletions, mitosomes, things like that. And the last patients were generally patients with very few cytogenetic abnormalities, but often a number of gene sequence mutations that were highly recurrent. So in this study, there were over 150 targeted gene sequences that they looked at and they found mutations in the majority of those genes, but each patient would only have maybe 3, 4, or 5 mutations in their leukemia present at diagnosis.

Looking at the patterns here, they were able to segregate patients into defining features even within this, and some of those were mutations that we’re very familiar with—nucleophosmin being one, CEBP alpha double mutations being another. There’s another group that has mutations that alter either the spliceosome complex or the chromatin remodeling. So, there’s a group of patients who have different functional mutations, but very similar prognostic grouping. From this, you could basically define, I believe, 11 different categories of patients based on where they fell in that; whether they had recurrent gene fusions in the specific lesion, the presence or absence to aneuploidy being a defining lesion. And then, if they had gene sequence mutations, where they fell there was highly prognostic to how patients did.
This is a huge and very complicated study. It really is interesting, because if you look at the patients, especially in the third group of a gene sequence mutation, it goes way beyond what we currently have for prognostic models. It can look at not only 1 gene mutation that’s prognostic, but also at combinations of 2 at a time or 3 at a time to say how patients will do. That goes beyond our current prognostic categorization, either by the NCCN or the ELN guidelines. I think that is notable, because it’s those combinations not of just 1 gene, but several genes together, that really tell us how that group is going to do.

Harry Erba, MD, PhD: What I thought was interesting about that analysis was that some of the data were quite consistent with data coming from other studies. For example, the group of patients who she identified from that study with mutations in the genes for spliceosome enzymes and chromatin modifiers—that same group of enzymes, or gene mutations, have also been identified as being more specific for secondary acute myeloid leukemia based on data published by Coleman Lindsley from a prior study of secondary acute myeloid leukemia.
The other thing is when we look at clonal hematopoiesis of indeterminate prognosis, those are the same classes of mutations that are occurring and may underlie some of the explanation of why our older patients who finally develop acute myeloid leukemia are doing so poorly.

Alexander E. Perl, MD: Yes, certainly, if you look at the gambit of who winds up with which lesion, older patients are much more likely to wind up with that third group that’s defined by its specific gene mutations, and often that arises out of clonal hematopoiesis of indeterminate potential, or CHIP. Or, they’re patients with aneuploidy and p53 mutations. And yes, you can see secondary leukemias, or secondary myeloid neoplasms, with either of those 2 groups. You can actually see them with the gene fusions as well, often after topoisomerase II poisons or anthracyclines.

Transcript Edited for Clarity 
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