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Understanding Genetic Mutations and Immunotherapy for AML

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Published on November 6, 2020

What Role do Genetic Mutations Play in AML Treatment Options?

Acute myeloid leukemia (AML) is not one entity, but rather a group of disorders with many possible genetic mutations. Hear a doctor and medical expert explain what these different genetic mutations mean for AML patients, in this excerpt from a recent AML virtual town meeting. This video breakdown includes the types of genetic testing for AML, the targeted therapies that are available for commonly occurring genetic mutations, and the role of immunotherapy in AML treatment.

Dr. Jessica Altman is a professor of Medicine in Hematology and Oncology, and director of the Acute Myeloid Leukemia program, at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

This program is sponsored by AbbVie, Inc. and Genentech, Inc. These organizations have no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

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Transcript | Understanding Genetic Mutations and Immunotherapy for AML

Dr. Altman: Acute myeloid leukemia (AML) is not one entity. It is a heterogeneous group of disorders, the way we think about it now, and the disease is driven by genetic alterations. So, there are some alterations that we call cytogenetic abnormalities, and we've known about them for decades. And over the last handful of years, we have understood that the cytogenetics do not fully represent the genetic abnormalities we see in patients' leukemia cells. There are also mutations in the genetic structure or the DNA of the leukemia cells.

What Are the Types of Genetic Testing for AML?

And so, we test for genetic abnormalities by doing two large groups of studies, the cytogenetics and molecular profiling, and the molecular profiling is frequently done by something called next-generation sequencing, where we can look for large numbers of mutations all at the same time.

Targeted Therapies for Genetic Mutations

There are some mutations and some set of genetic abnormalities that impact the initial treatment. So, the genetic information both impacts prognosis and can impact therapeutic recommendations. The genetic abnormalities, some of them impact our initial treatment. For instance, if the disease expresses a FLT3 mutation, FLT3 mutations are relatively common, one of the most common genetic abnormalities we see, and are present in about 30% of adults with newly diagnosed acute myeloid leukemia. That mutation is targeted with the addition of a pill called midostaurin (Rydapt) for initial treatment, and adults who receive standard 7+3 chemotherapy.

There's also a FLT3 inhibitor that is approved for relapsed FLT3 mutated disease. That drug is called gilteritinib (Xospata). So, that is one example of how it's important to know what the molecular abnormalities are at first presentation. They also impact later therapy in terms of what standard of care options or clinical trials are available for relapsed disease. In addition, because of the impact on prognosis, it helps us think about the role of stem cell transplant from the beginning.

 

What Does the WT1 Genetic Mutation Mean for AML Patients?

So, there's a little bit of controversy about WT1, and maybe let me preface this by, I wish it were as easy as mutation A leads to prognosis X in every single situation. But because there are so many genes that are mutated in leukemia, we need to think about not just single mutations, but how the mutations interact together. So, what we do know, and normal cytogenetic AML, that means AML without other chromosomal abnormalities, that WT1 may be associated with a less favorable prognosis, but there are so many ... That's in the absence of thinking about all the other mutations, and so it's not really fair to think about WT1 alone. WTI has been interesting because it can also be utilized to think about the ... When it's gone, it's equivalent in some instances to the disease being in an MRD negative state. So, it can be a marker for very deep response to treatment.

What Does the RUNX1 Genetic Mutation Mean for AML Patients?

RUNX1 or RUN-X1, it is a gene that is mutated in some forms of acute myeloid leukemia. There are some agents that we're studying that look like they might have increased sensitivity in patients whose disease expresses the RUNX1 mutation that's exceptionally early and really based on a little bit of laboratory data. And those are agents that are really early in clinical development. So, I would like to assure everyone who's listening that when we talk about a clinical trial, we are at the point where we are not just testing a drug that we think has promise in all of AML. We are specifically thinking about a patient's molecular mutational profile and trying to choose the best clinical trial, either based on laboratory data or some early clinical trial data.

What Does the NPM1 Genetic Mutation Mean for AML Patients?

 So NPM1 stands for a nucleophosmin 1. It is a mutation that is relatively common, especially in acute myeloid leukemia with no chromosomal abnormalities. When it is by itself or with specific other mutations, is associated generally with a more favorable prognosis. Now, I think it's really not kind to say anything in acute myeloid leukemia is favorable, it's a horrible disease to go through, but so if I flip into saying something is favorable, you'll excuse me because that's the nomenclature. I prefer to talk with my patients saying that something is less unfavorable, but then we get into all sorts of double negatives and that's confusing.

Could the Results of an AML Patient’s Genetic Testing Change after Remission?

At times of recurrence, the molecular profiling should be reevaluated. There are some mutations that are not present at presentation but are seen later. It's not really clear that they're not actually present at diagnosis or initial diagnosis. It might be that they're below a level that we don't pick up on clinically. And that may be a clone at the time of relapse that has grown. And so, it's important to reanalyze to see if there are mutations, especially if there are mutations that can be targeted with an available standard of care drug or with an agent in a clinical trial.

Are There Immunotherapy and CAR T-Cell Therapy Options for AML Patients?

Stem cell transplant is the most aggressive immunotherapy that we have. The role of a stem cell transplant is to replace one's own immune system with a new immune system that can fight any leukemia cells that come back, that's one of the goals of the stem cell transplant, in addition to the high doses of chemotherapy to kill any lurking leukemia cells. So, for leukemia, we've had a pretty aggressive immunotherapy that has been utilized for many years.

There are other agents that are being studied that are immunotherapy agents. So, some of the approved immunotherapy drugs are being studied in combination therapy in acute myeloid leukemia. There also are some novel antibodies. Antibodies are part of the immune system. What antibody therapy does in acute myeloid leukemia is to help target specific abnormalities on leukemia cells. And so, there are a couple of antibody therapies that are currently ongoing in clinical trials to try to harness the immune as well.

So, CAR T-cell studies are ongoing in acute myeloid leukemia. It is not ready for prime time and very early in development. And part of that is really due to the heterogeneity of the acute myeloid leukemia cells and not having as often a common thing to target like in lymphomas and acute lymphoblastic leukemia (ALL). But similarly, some of these antibody studies are trying to target those abnormalities as well.

There are things that we didn't even know to think about years ago. So, we are looking at new methods of maintenance therapy in acute myeloid leukemia. There's one drug that's approved as a maintenance therapy in acute myeloid leukemia. But we're looking at other agents as well. So those were areas that we hadn't previously thought of. There's also a major interest in trying to clean up the disease a little bit before stem cell transplant, what we call MRD erasers, we've mentioned MRD previously. 


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