Hetty Carraway, MD
Results of a deep sequencing analysis demonstrated that mutations in 8 high-risk genes are associated with an acute myeloid leukemia (AML) diagnosis. These findings, explained Hetty Carraway, MD, lay the ground work for early detection studies and novel treatment strategies.
“It is pretty provocative work, pretty exciting, and it really allows us to think more deeply about how we can impact and change that trajectory for patients,” said Carraway, who is vice chair of Strategy and Enterprise Development at Taussig Cancer Institute, Cleveland Clinic.
In the study, researchers identified 212 women from the Women’s Health Initiative who eventually developed AML at a median follow-up of 9.6 years. Deep sequencing was performed on peripheral blood DNA and compared with age-matched controls that did not develop disease. Results showed that mutations in IDH1
were significantly associated with an increased risk of developing AML.
Moreover, all patients with TP53
as well as IDH1
mutations eventually developed AML. The presence of these identified mutations years before an AML diagnosis suggests that there is an inactive period that precedes AML, the authors concluded.
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Hematologic Malignancies, Carraway highlighted ongoing genomic research in AML, as well as recent therapeutic advances in the field.
OncLive: What is the prevalence of actionable mutations in AML?
: Things that are really important to remember in the treatment of patients with AML is to think about doing mutation testing by next-generation sequencing for patients at the time of diagnosis, as well as at the time of relapse. These types of mutations can inform how patients will do in terms of prognosis, and it can also inform choice and selection of therapies for them.
Another thing to remember is that as we get novel therapies, know that clinical trials are going to be very important in order to better understand how to combine these [treatments], how to optimize response, and to be mindful of the toxicities that may happen as a result of combination therapy.
In your presentation, you highlighted research about mutations that can predict AML before it is actually diagnosed. Could you discuss that?
There has been some fascinating work on the presence of mutations in patients who do not have a hematologic malignancy—to understand the presence of mutations and clonal hematopoiesis of indeterminate potential. [They looked at the] patients that evolve from having these particular mutations that then go on to have dysplasia, that then go onto have clonal events, that then lead to myelodysplastic syndrome (MDS).
Then, there are specific mutations that those groups went on to identify to be more associated with a higher risk of progression to disease, such as hematologic malignancies. They also found that there was an increased risk of cardiovascular disease, early myocardial infarction, and stroke by twofold. That work was really seminal in other groups who then tried to ask, “Well, let’s look at larger cohorts of patients. Are there patients who had AML as a result [of these mutations]?”
Work by Pinkal Desai, MD, et al, and another group went on to look at larger cohorts of patients and identify those who were diagnosed with leukemia. Then, they went back 10 years before that diagnosis and looked at serial samples of blood to say, “What happened with the detection of mutations?” They were able to identify differences in patients over that time span in the presence of mutations and the variant allele frequency, the types of mutations, and the double mutations in specific genes that then predispose, or what could be used as identifiers, in saying that those patients were likely to progress to AML compared with those patients who did not have AML and did not have those mutations.
That brings up an interesting point. Could this knowledge help prevent the disease from occurring in the first place?
It really is a whole different way to think about things that we have not really had the luxury of thinking about previously. The other side of that, which many excellent researchers are working on, is after you give patients chemotherapy, can you really evaluate minimal residual disease in this population? Can we do things earlier, so that they can be cured—or change the outcome for them in terms of relapse?