FLT3 Mutation Status in AML

Transcript:Hervé Dombret, MD: Among the gene mutations that have been discovered by sequencing the blast genomes, FLT3 genes appeared very rapidly as a bad-risk mutation. So, basically, when there is a mutation in that gene, the leukemic cells have a tendency to proliferate and to not die. This is really a bad-risk mutation. Curiously, the complete remission rate is not so different in patients with FLT3 mutation as compared to patients without FLT3 mutation, but the risk of relapse is much higher in patients with the mutation. It has been one of the first targets to target with molecules that could inhibit the FLT3 kinase, and midostaurin has been one of the first drugs developed for that. What is expected when using FLT3 inhibitors, and especially midostaurin, is that you can prevent the relapse in these patients. And, actually, it works. It’s not black or white or yes or no, but giving midostaurin in combination with the standard treatment during induction, during consolidation, and then during a maintenance phase, allowed us to prolong survival of the patients.

Richard M. Stone, MD: Using FLT3 as a target in developmental therapeutics for AML has both good and bad aspects. It’s a good aspect in the sense that it’s a common mutation. FLT3 ITD occurs in about 25% of AML patients and FLT3 TKD is in about 10%. They’re both activating mutations, which means they’re gain-of-function mutations. So, if you have a gain-of-function mutation, you can presumably inhibit it. It’s probably important to the pathophysiology of AML, so inhibiting it might be advantageous, therapeutically, as much as inhibiting the activated tyrosine kinase called BCR-ABL in CML (chronic myelogenous leukemia). That’s the good part. The bad part is that it’s a relatively late hit in the development hierarchy of AML. In other words, it may not be a founder mutation. It’s not going to be the first mutation that leads a stem cell on from a good path to a bad path, and being an AML stem cell, if it’s a late hit, inhibiting it might just pair down the problem back to the original first hit or few hits. So, that’s one issue.

The second issue is that the disease can evolve over time, or, more specifically, you can have what’s called clonal selection. You might select 4 clones that are different than the ones that were present at the time of diagnosis. A good example of that, in terms of FLT3, is that you might have an FLT3 mutation at diagnosis, give an FLT3 inhibitor, give regular chemotherapy, and then the patient relapses with FLT3 wild-type disease, implying that inhibiting the FLT3 is not going to be such great shakes, after all. And, yes, there are some patients who don’t have FLT3 mutations when they’re diagnosed, who get chemotherapy or some other therapy, and then when they relapse, they have an FLT3 mutation, implying that you missed an opportunity to inhibit their FLT3 with an agent that would not be used since they didn’t have an FLT3 at diagnosis.

Hervé Dombret, MD: With FLT3 mutations, it is important to consider that when a patient comes in with a diagnosis of leukemia, it occurs relatively frequently that FLT3 mutation is not present in all the blast cells, but sometimes only in a subset of the blast cells. This is called the FLT3 allelic ratio. This is addressed by measuring of the FLT3 allelic ratio. So, you can have patients with low-allelic ratio, meaning that the mutation is present only in a minority of blast cells, and some of the patients with high-allelic ratio, meaning that the mutation could be present in all the leukemic blast cells. And this is different in terms of prognosis. This is a matter of debate, currently. How do you define what is a bad-risk FLT3 mutation? Does allelic ratio play a role? Probably, yes. This heterogeneity within a single subset of AML, which is AML with an FLT3 mutation, is also important to consider, not to mention the fact that there are several FLT3 mutations. The most common is so-called internal tandem duplications, ITD, but there are others. The risk associated with this different mutation also could be valuable.

What is important is this suggests the fact that the mutation could be present only in a minority of cells. This suggests that FLT3 mutation is not a driver mutation. It is not present at the beginning in the development of leukemia, but could be a secondary mutation, a passenger mutation that is present; then, after that, can occur in a subclone of the disease. What is interesting is that when the patient with FLT3 mutation relapses, usually the allelic ratio increases, meaning that the cells with the mutation are the cells with the potency to survive and to then proliferate. This is a higher potency as compared to the subset of cells without the mutation. So, usually, at relapse, the importance of the ratio of the mutation is higher than at diagnosis.

Transcript Edited for Clarity