Prognostic Impact of FLT3 Mutations in AML

EP: 1.Overview of FLT3-mutated AML

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EP: 2.Prognostic Impact of FLT3 Mutations in AML

EP: 3.Testing for FLT3 During Relapse in AML

EP: 4.Using Second-Generation FLT3 Inhibitors in R/R AML

EP: 5.Optimizing Use of FLT3 Inhibitors in AML

EP: 6.Phase 3 QuANTUM-R Study in R/R AML

EP: 7.Importance of Achieving CR in AML

EP: 8.Combination Sorafenib Plus HMA in R/R AML

EP: 9.Developing Resistance With FLT3 Inhibitors in AML

EP: 10.Treatment Combinations in FLT3-Mutated AML

EP: 11.BCL2 Inhibitor Combinations in FLT3-Mutated AML

EP: 12.Emerging Combinations for FLT3-Mutated AML

Jessica K. Altman, MD: I know we’re trying to gear our conversation today toward FLT3 mutations. Does your practice parallel what we see in the general US population, that the ITD [internal tandem duplication] mutations are present in about 20% to 25% of cases and the TKD [tyrosine kinase domain] mutations comprise another 5% or so of patients?

Naval G. Daver, MD: Yes, absolutely. As you said, that is the most common mutation of FLT3. Especially in younger patients—below age 65—as has been published, we see that 30%, 35% will have a FLT3 mutation; the more common is the ITD, of course. ITD mutations comprise 80% of all FLT3 mutations. TKD may be about 15% or so of all FLT3 mutations. That is probably the most important molecular mutation we wait for, because it can impact our frontline therapy.

Also, interestingly, we are now starting to see some of these noncanonical FLT3 mutations. There are some recent data published, although their prognostic therapeutic significance is still unclear. There are many of them, but for some of them now there are data. If we see things like N676 or N841, then we are considering using FLT3 inhibitor-based therapies up front.

How is your FLT3 reported? Is it usually reported based on PCR [polymerase chain reaction] testing? What is the sensitivity? How do you use that information? If it’s very low burden, do you ignore it? Do you use a cutoff point?

Jessica K. Altman, MD: If you recall, the RATIFY trial required an allelic ratio of 0.05. If I have a choice, in terms of treatment options, I try to follow what was done in the clinical trials. For instance, I recently had an older patient who was fit for intensive chemotherapy. She was in her late 60s. I had 2 clinical trials that she would have been eligible for: a FLT3-directed clinical trial and an older adult clinical trial without a FLT3 inhibitor. She had a FLT3 mutation, but her allelic ratio was low—less than 0.05. Based on that information, she wouldn’t have been eligible for the RATIFY regimen. Because that was such a small component of the rest of her disease burden, I chose not to treat her with FLT3-directed therapy. I try to follow those data when I can. Certainly, if there isn’t another therapy available and another mutation to target, I might consider adding a FLT3 inhibitor. But generally, I try to follow the data. What about you?

Naval G. Daver, MD: I think this is a very interesting question. Traditionally, I do the same. If I have somebody with very low FLT3 allelic burden, whether it’s a ratio or frequency of less than 5% or 3%—some of the studies allow 3%—we would try to go for a non-FLT3 option. So let’s say it’s a younger patient for induction. I may prefer a clinical trial like FLAG-IDA [fludarabine, cytarabine, G-CSF, idarubicin], plus venetoclax, which is a trial we have open here and is quite exciting. What we’ve started to see, and we have a recent analysis on this, are cases of very low FLT3 burdens who may relapse with higher FLT3 because that clone is there. We haven’t really acted on it yet, but I think the question is emerging of, could these FLT3 inhibitors work in low burden or even wild-type patients? We have seen that wild-type patients may emerge with the FLT3 mutation. I think this will be an interesting research question as we go forward and follow these patients who get non-FLT3 or FLT3-based therapies.

Transcript Edited for Clarity