Combining and Sequencing FLT3 Inhibitors in AML


Harry Erba, MD, PhD; Courtney DiNardo, MD; Mark Levis, MD, PhD; and Vinod Pullarkat, MD, review factors to consider when using combining and/or sequencing first- or second-generation FLT3 inhibitors for patients with acute myeloid leukemia (AML).

Harry Erba, MD, PhD: Are there other FLT3 inhibitors that are likely to add benefit, either in terms of toxicity or efficacy? Mark, do you want to bring us through a discussion of that?

Mark Levis, MD, PhD: Well, we are still sorting out the ones that we have in front of us. Midostaurin, gilteritinib, and quizartinib are about to be thrown into the mix, and crenolanib is there. We have 4 of these things. Fortunately, we have randomized studies that are going to provide a lot of data. I will say there is another one coming. We have an irreversible drug that we have just started development on, and it seems to have activity in those cases that have had so much FLT3 inhibitor [that] they have lost FLT communication, and they are still addicted to FLT3. That is a drug that will be coming down the line. But in terms of sorting out the 4 big players out there now, wait for the randomized data. It's coming.

Harry Erba, MD, PhD: I think the major point here for the community is that at the time of diagnosis and when considering relapsed/refractory (R/R) disease, it is important to look for FLT3 mutation. Midostaurin with intensive chemotherapy followed by transplant seems to truly improve the outcome of these patients. In the R/R setting, we now have an approved agent, gilteritinib, and many of us are combining it with other agents to try to get deeper responses and still be able to get those patients to transplant. Testing comes first. You must think of testing before you think about using these drugs.

Vinod Pullarkat, MD: In community practices, there is this feeling that if you have an FLT3 mutation back, you have to use an inhibitor, right? Until we establish a combination of HMA [hypomethylating agents] and venetoclax with 3 inhibitors as a standard, you could still use HMA and venetoclax in the treatment of older, chemo-ineligible patients, and you do not necessarily need to use an FLT inhibitor. It is important to make that point, because, unlike solid-tumor situations, you are not completely mutation-driven when you choose these regimens.

Harry Erba, MD, PhD: You made that important point earlier. If the patient is truly unfit for intensive chemotherapy, you really do not need to wait for any cytogenetic or mutational data. Assuming that they have a performance status better than 4+, wherever that is, they should be treated with an HMA and venetoclax with a very high response rate, including [patients with] FLT3 mutations. I think [we] all realize that the poor prognosis of these patients with FLT3-mutated disease, and at least in the subset analysis that Marina Konopleva, MD, PhD, [of the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston,] presented at ASH [American Society of Hematology annual meeting], there is no difference in survival between patients treated with HMA [and those given] azacytidine alone or azacytidine with venetoclax for FLT3 mutations. Their median survival was shorter than [for] the entire group. We clearly need other options, and these patients need to be considered for transplant. They are not transplant candidates when they show up, and I think we would all agree that we need to keep this in the back of our mind. Once they achieve remission, they may become transplant candidates.

Vinod Pullarkat, MD: To Mark's point, if we prescribe the inhibitor in addition to venetoclax, and it is going give me more MRD [minimal residual disease], then that would become my standard of care. My focus right now would be to try to take them to transplant and get them into remission as soon as possible.

Mark Levis, MD, PhD: If you add the FLT3 inhibitor to HMA, then the patient is often left with smoking ruins even though they have MLFS [morphologic leukemia-free state]. You will kill everything. At least for the older patients, upfront, I know we have had lots of discussions with [The University of Texas MD Anderson Cancer Center] colleagues about this, but I prefer to use the so-called “triplet” in the relapse setting.

Courtney DiNardo, MD: One of the most important things that will come over the next few years is trying to figure out how to best use these effective therapies together or in appropriate sequences. HMA with venetoclax has activity for patients with FLT3 mutations. Clearly, FLT3 inhibitors have activity. The initial approval of HMA [plus] venetoclax [entails] continuous 28-day venetoclax cycles forever and ever. When you are adding another agent, is that the right thing to do, or is it going to lead to such significant myelosuppression that you cannot add these other agents? Is that the right thing to do? I think this is where we are still having a lot of differences of opinions, because we do not have the data yet, and different institutions are doing things a little bit differently.

Harry Erba, MD, PhD: I agree. In my limited experience with this combination—one I have had to use for more refractory patients—when combining an FLT3 inhibitor with venetoclax with or without an HMA, you really need to cut back on the duration, perhaps, of both drugs—venetoclax and gilteritinib—and give patients breaks to allow some count recovery. Otherwise, as Mark said, you leave them in smoking ruins with MLFS. That would be great if they were in a phase 1 study, but not if they are in your clinic.


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