ASH 2024 | Results of a Phase II study of gilteritinib versus midostaurin in newly diagnosed FLT3-mutated AML

FLT3 mutations are the most common mutations seen in newly diagnosed acute myeloid leukemia, and the most common FLT3 mutation, internal tandem duplication, unfortunately portends a poor prognosis for patients with acute myeloid leukemia. 

The RATIFY trial demonstrated that adding midostaurin to standard induction therapy improves survival in patients with AML who have FLT3 mutations. However, we all know that midostaurin is not a very specific or potent FLT3 inhibitor. There are newer generation FLT3 inhibitors and one of them is gilteritinib. And gilteritinib has been approved for use in patients with relapsed and refractory FLT3 AML because it improves survival in that patient population. So we wanted to ask the question of whether using gilteritinib rather than midostaurin in patients with newly diagnosed AML with FLT3 mutations would improve the outcomes, given that it is a more potent and stronger and more specific FLT3 inhibitor. 

So we chose to ask investigators to send for central analysis marrows on any patient in whom they suspected acute myeloid leukemia. Centrally, we did FLT3 mutation testing and NPM1 mutation testing, and patients who had a FLT3 mutation were then chosen to be on trial and randomized to either receive standard chemotherapy with daunorubicin, cytarabine, and midostaurin, or standard chemotherapy with daunorubicin and cytarabine and gilteritinib. 

We initially included patients only up to the age of 65, and we later allowed patients up to the age of 70. The inhibitor, either midostaurin or gilteritinib started on day eight. We initially required that results be available from the central testing before patients could be enrolled on the trial. However, we later decided that we would allow patients to start chemotherapy as long as they receive the same agents and the same doses of daunorubicin and cytarabine and enrolled in the trial before the randomization needed to happen by day eight. So those were two of the early amendments that were made. 

A total of 177 patients were enrolled in the trial. And again, half received midostaurin and the other group received gilteritinib. The primary endpoint of the trial, we decided in order to get a quick look, we wanted to see what the outcome was in terms of the likelihood of becoming FLT3 mutation negative at the time of complete remission after one course of therapy, after induction therapy, which could be one or two cycles of induction chemotherapy. So all patients were assessed again for presence of the FLT3 mutation centrally at the end of induction therapy, and that was our primary endpoint, FLT3 mutation negative complete remission, or composite complete remission. 

We also had secondary endpoints, which were just the remission status itself, looking at measurable residual disease by flow cytometry, which is considered the standard way of looking at measurable residual disease in AML. And later on in the trial, when we learned more about the kinetics of FLT3 mutations and MRD, we decided to look at mutation status at the end of the first cycle of high-dose cytarabine consolidation. Patients after induction who were in a complete remission or complete remission with incomplete recovery of counts could proceed to high-dose cytarabine consolidation, again, with either gilteritinib and midostaurin, depending on what they were randomized initially, and they could also proceed to allogeneic transplant at any time once in remission. They received the TKI with consolidation therapy, they did not receive TKI after allogeneic transplant. 

In this trial, we were able to demonstrate a very, very high remission rate with over 85% of patients achieving a complete remission if they received daunorubicin, cytarabine, and gilteritinib. And there was a higher number of patients achieving a composite complete remission if they received daunorubicin, gilteritinib, compared to daunorubicin, cytarabine, and midostaurin. And if we looked at flow cytometry for MRD, we similarly were able to show that more patients who received daunorubicin, cytarabine, and gilteritinib achieved a flow MRD negative remission compared to those who received daunorubicin, cytarabine, and midostaurin. However, our primary endpoint was MRD negativity by FLT3 mutation analysis, and we were not able to show an improvement by MRD analysis by FLT3 mutation for those who received gilteritinib compared to those who received midostaurin. 

However, we also looked at subsequent therapies and we were able to demonstrate that more patients who received gilteritinib went on to receive consolidation therapy and more patients who received gilteritinib went on to receive allogeneic transplant, which we know is critical in the long-term care and survival of this patient population. 

So really what we learned from this trial is that we can achieve very, very high remission rates with daunorubicin, cytarabine, and gilteritinib in patients up to the age of 70, and that the majority of patients who receive that regimen are able to proceed to allogeneic transplant in first remission. What we don’t know is how does that impact survival, and we also don’t know when should we really be looking at MRD negativity by mutation in order to best understand its impact on survival.

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