Combinations are the Future in FLT3-Mutated AML - Episode 5
Experts in leukemia comment on the utilization of FLT3 inhibitors in combination with chemotherapy in early and recurrent acute myeloid leukemia.
Naval G. Daver, MD: What do you think the next steps are, and how can we build here?
Jessica K. Altman, MD: Those are really great questions. I want to try to delve into a bunch of your questions. I’ll start with the last question you alluded to—how can we do better? I think there are a number of things for which we need to think about doing better. I think it’s utilization of FLT3 inhibitors early in treatment, whether that’s using 7+3 [daunorubicin plus cytarabine] and midostaurin. In the ADMIRAL study, only about 12% or so of individuals had received a prior FLT3 inhibitor. That might impact response rate. So, utilization of a FLT3 inhibitor early in combination with chemotherapy with the goal of never needing a treatment in relapse. The goal is getting a fit, appropriate patient to transplant. And then, if the data show what we hope it will—that the use of a FLT3 inhibitor post-transplant will improve survival—we need to consider the utilization of a FLT3 inhibitor post-transplant, hopefully minimizing the number of patients who have recurrent disease. So, doing better initially.
But also, trying to do better at the time of recurrence. You and I have both been interested in adding things onto gilteritinib or other FLT3 inhibitors, which we’ll talk about. So we need to consider using something that’s more potent at the time of recurrence in combination, and getting a better understanding of the mechanisms of resistance. We used to, and we still do, worry about the development of a TKD [tyrosine kinase domain] mutation, or clonal evolution, as a cause of resistance. We don’t see that as much with gilteritinib and crenolanib compared to midostaurin and quizartinib because they inhibit TKD mutations. But there are other point mutations that can occur. I’ll stop here and get your thoughts on how to do better with the available FLT3 inhibitors and available agents we have. And then you can walk us through the data from QuANTUM-R, quizartinib, because I know you and your colleagues have been critical in the development of quizartinib.
Naval G. Daver, MD: Absolutely, I completely agree. We’re at a stage where we have now these very effective drugs. As single agents, each of these will give us modest improvement. If we can find, and I think we can, the right way to combine or sequence them, hopefully we can improve the cure rates. As you said, you, me, and other colleagues are working on these things in studies.
I’m really interested in the frontline studies where we incorporate even better FLT3 inhibitors, second-generation ones with chemotherapy—whether it’s gilteritinib or quizartinib, or whether it’s 3+7 [daunorubicin, cytarabine] or FLAG-IDA [fludarabine, cytarabine, G-CSF, idarubicin], or CLIA [cladribine, idarubicin, cytarabine]. I think all are good, and we get a deep molecular clearance. And as you now know, the FDA and other authorizing entities are becoming more and more interested in this. They haven’t yet approved or accepted it, but I think there’s high interest, especially for these molecular targets where we can see very high sensitivity and show clearance, which hopefully will then be confirmed with survival. I think, like you said, if we can avoid relapse, this will be 80% of the battle won. Maybe using these in the frontline setting will be an effective approach.
Jessica K. Altman, MD: I’m going to interrupt for one moment and underscore one thing that you said, because it’s timely. There are ongoing clinical trials that focus in the community and that academic centers can participate in. In the US, we have the study of 7+3 [cytarabine, daunorubicin] with either midostaurin or gilteritinib. There’s also an ongoing large phase 3 clinical trial of crenolanib versus midostaurin. Those are studies actively recruiting patients. Patients receive at least 7+3 [cytarabine, daunorubicin] and midostaurin, the standard of care. The alternative arm is a FLT3 inhibitor, which at least in relapsed disease, we think is more potent. We don’t know if it will result in an improvement when used in the frontline setting, but those next-generation FLT3 inhibitors have all been shown to be able to be safely combined with upfront intensive induction chemotherapy. So, those single-arm studies have been conducted and reported on.
Naval G. Daver, MD: Yes, absolutely. I think those are critical studies. If we just treat with 3+7 [daunorubicin, cytarabine] and midostaurin in the community, we will never know if 3+7 [daunorubicin, cytarabine] and gilteritinib, or 3+7 [daunorubicin, cytarabine] with crenolanib, or 3+7 [daunorubicin, cytarabine] and quizartinib will be better. Intuitively, many of us think that given their single-agent activity where you can get 50% marrow remission versus 5% or less with midostaurin/sorafenib, we think this will translate into more potent activity. Now yes, these are more targeted. The others are multikinase, so there could be a contrary discussion. But I do think those trials are critical.
Transcript Edited for Clarity