The Emerging Role of FLT3 Inhibitors in AML and ASM - Episode 1

Genetic Complexities in AML

Transcript:Hervé Dombret, MD: During the last few years, we have learned a lot on the genetic events occurring in AML. So, it has been based mostly on deep genomic sequencing of the blast cells in evaluating a large population of patients. And, what we learned is that it’s not only a single disease, it’s a lot of different subsets based on genetic abnormality. That’s the first important point. The second one is that this mutation could have been classified as, let’s say, driver mutation and secondary, or passenger, mutation. This is really important from our particular point of view because it’s obvious that probably targeting driver mutation could be more efficient than targeting passenger mutations.

The occurrence of AML in some patients, especially older patients, could be preceded by a phase of myelodysplasia, a disease in the bone marrow that is not yet an acute leukemia. This is called myelodysplastic syndrome. In older patients, it’s quite frequent that AML is occurring after a phase of myelodysplasia. And for a long period of time, this has been recognized, but we do not really know how to define and to discriminate this patient as compared to de novo AML occurring in a patient without myelodysplasia. Because to know that there is a previous myelodysplasia, you have to have access to produce a bone marrow examination, which is not the case in most patients. Although doctors used to call it a secondary leukemia, leukemia at diagnosis, there are some myelodysplastic changes in the different hematopoietic lineages. The true definition of what could be called ‘secondary leukemia’ came when you knew the mutation and the mutational status. And, now, based on mutational status in each individual patient, it’s more easy to define what is really a secondary leukemia as compared to a de novo leukemia. So, mutational analyses have been very useful to solve this issue.

Richard M. Stone, MD: There happen to be about 30 or so recurrent mutations in AML. The average case has about 3 to 5 of those. However, right now for prognostic purposes, the average clinician should send off studies to assess the status of the mutations in the following 4 genes: FLT3, c-KIT, NPM1, and CBP-alpha, because those are the ones that have current prognostic importance. Specifically, biallelic mutations in CBP-alpha have a favorable prognosis. Mutations in NPM1 have a favorable prognosis. Mutations in c-KIT, in those who also have a core binding factor cytogenetic abnormality, including inversion 16 (inv(16)) or 8;21 translocations (t(8;21)), have a negative effect on that subgroup. Finally, the FLT3 internal tandem duplication, or ITD mutation, which occurs in about 25% of AML patients, overall, has a clearly adverse effect on prognosis.

Approximately 30% of AML patients’ blasts can be shown to harbor an FLT3 mutation. There were 3 subtypes of FLT3 mutations. The more common subtype, which accounts for approximately three-quarters of all FLT3 mutations, is an internal tandem duplication mutation, or a repetition of between 3 and over 100 amino acids in the juxtamembrane region just inside the cell relative to the cell membrane. This type of mutation carries an adverse prognosis. Patients who have it tend to relapse at a higher rate than their non-FLT3—mutant colleagues, and also have an inferior overall survival. The other type of mutation, which occurs in 25% of those with a FLT3 mutation or about 10% overall of AML patients, is called an FLT3 TKD, or tyrosine kinase domain mutation. The prognostic impact of that mutation is controversial. Some studies have shown it to be adverse, others have shown it to be favorable.

Transcript Edited for Clarity