Combinations are the Future in FLT3-Mutated AML - Episode 3
Leukemia experts discuss the role of genetic testing to check for FLT3 mutations at the time of relapse in acute myeloid leukemia.
Naval G. Daver, MD: One more thing to add about testing, in the community, there are 2 FLT3 inhibitors approved. One is frontline midostaurin. As you mentioned, based on RATIFY study, 3+7 [daunorubicin, cytarabine]/midostaurin versus 3+7 [daunorubicin, cytarabine] showed that the addition of midostaurin improved remission rates when we looked at all remissions over time. And importantly, the regimen improved survival and got approval. Then you have salvage gilteritinib, which was approved based on the phase 3 ADMIRAL study. One of the things I’ve seen is that in relapse, a lot of times people are not checking for FLT3 mutations in the community. What’s your practice and advice for patients who relapse? Would you test all the time or not?
Jessica K. Altman, MD: That’s a very important point. I strongly recommend retesting at the time of relapse. Just as you mentioned, there may have been a FLT3 mutation previously at diagnosis, but the sensitivity of the test didn’t pick it up. Then it’s present at the time of relapse and may be what’s driving the recurrent disease. Or, it is a new mutation. We won’t ever really know the answer to that, but I think it is absolutely critical to retest, for especially the actionable mutations, at the time of recurrence. For a patient who has multiply relapsed disease or refractory disease, depending on the tempo of the disease, I recheck in the future, at a time when I’m having to make a new treatment decision. I don’t do this for every patient, but there are times when you may be sparked to be concerned that the next recurrence or that highly refractory patient has acquired a FLT3 mutation, and we’ve seen it.
Naval G. Daver, MD: Absolutely. I had 2 patients in the last maybe 3, 4 weeks who, just as you said, were multiply relapsed. They had gone through 3 or 4 treatments and started having proliferative features. We checked for FLT3 in both of them, and both of them had an emergent FLT3 mutation. This was very good for the patients and for us, I think, because now we have a very effective targeted option, combinations with FLT3 inhibitors and venetoclax, and they’re both on that. I totally agree. For the community team out there, it’s critical to check for FLT3 at relapse. Definitely at first relapse, I would check in everybody. This is where the ADMIRAL data were. And even in subsequent relapses, if you have the ability, or as you were saying, Jessica, if there’s a suspicion based on proliferative or very high blast or high white blood cell count, it’s good to check. This may be the only option left by the salvage 2 or 3 therapy.
Jessica K. Altman, MD: I agree. Even if a patient’s disease has 1 mutation, they may have another mutation as well. For instance, in individuals whose disease is characterized by an IDH mutation, it is not uncommon at the time of relapse from an IDH-mutated disease to see a FLT3 mutation. And so, just because your disease had an IDH mutation or a different mutation doesn’t mean it can’t acquire a FLT3 mutation. And so, even in patients who’ve received other targeted therapies, we should continue to test.
Naval G. Daver, MD: And even the converse is true. Recently, at the ASH [American Society of Hematology] meeting, we saw data presented on the use of 3+7 [daunorubicin, cytarabine] plus sorafenib. At relapse, of the people who had received induction with the sorafenib/FLT3 inhibitor regimen, only 50% to 55% still had a FLT3 mutation. We have also seen this with the RATIFY data. I think outcomes may even be more with some of the trials that incorporate more potent FLT3 inhibitors like gilteritinib, quizartinib.
Again, in the community, just because somebody had a FLT3 mutation and you gave them 3+7 [daunorubicin, cytarabine]/midostaurin and they relapsed a year later, I would not give them a FLT3 inhibitor right away. I would check, because almost half of them could lose the FLT3 mutation. The bottom line is, at the time of relapse check for FLT3, IDH1, IDH2, and even maybe TP53, for which there are trials moving forward.
Transcript Edited for Clarity