FLT3-ITD and
FLT3-TKD mutations are common mutations in AML with frequencies of 20–25% and 6–10%, respectively [
25,
26]. Importantly, they are unstable mutations that are frequently lost or gained at the time of relapse.
FLT3-ITD specifically is a strong adverse prognostic marker at the time of relapse and only a minority of
FLT3-ITD-positive patients can be cured at the time of relapse despite aggressive salvage therapy [
27]. Due to the strong independent adverse effect,
FLT3-ITD mutation status has been integrated into the prognostic GOELAMS score [
4]. Thus, targeting FLT3 with the aim of overcoming the adverse prognostic effect is attractive. Several tyrosinkinase inhibitors have been developed with activity against FLT3 [
28]. The first-generation TKIs (e.g., sorafenib, midostaurin) are multitarget inhibitors that function relatively unselectively against FLT3. In contrast, the next-generation TKIs (gilteritinib, quizartinib) have a stronger selectivity for FLT3 [
28]. Due to the positive results in the RATIFY trial [
29], midostaurin has been approved for
FLT3-mutated AML in first-line therapy in combination with intensive chemotherapy by the FDA and EMA. It is now standard treatment for newly diagnosed FLT3-mutated AML patients in combination with intensive therapy [
29]. However, midostaurin and sorafenib have little activity as monotherapy in relapsed patients [
30,
31]. However, next-generation TKIs have shown antileukemic single-agent activity in early clinical trials [
28]. Gilteritinib is an oral type 1 FLT inhibitor that was first investigated as monotherapy in 252 r/r AML patients in a phase Ib/II trial [
32]. Patients with
FLT3 mutations had the best response with an ORR of 49% compared with 12% in
FLT3 wild-type patients. These promising results in
FLT3-mutated AML have led the way for a large randomized phase III trial in r/r
FLT3-mutated AML. Here, monotherapy with gilteritinib was compared with chemotherapy (ADMIRAL trial) [
33••]. Chemotherapy in the control arm was performed according to the investigators choice with MEC (mitoxantrone, etoposide, and cytarabine), FLAG-IDA, LDAC, or azacitidine. Of the originally 371 patients enrolled in the trial, 247 patients received gilteritinib and 124 patients standard chemotherapy. The CR rate was 21.1% with gilterinib compared with 10.5 in the comparison arm. Median OS was significantly better in the gilteritinib compared with standard therapy arm (9.3 versus 5.6 months) and 1-year OS was 37.1% versus 16.7%, respectively. The EFS was 2.8 months in the gilteritinib arm and 0.7 months in the control arm. The best results were obtained for patients proceeding to transplant and continuing gilteritinib treatment thereafter. Importantly, subgroup analysis of the trial showed that a response to gilteritinib was also seen in patients with prior use of FLT3 inhibitors while patients with unfavorable cytogenetics did not seem to benefit. The results of the ADMIRAL trial were the basis for the approval of gilterinib in r/r
FLT3-mutated AML by the FDA. We would recommend gilteritinib for patients with
FLT3-mutated r/r AML if accessible. Quizartinib is also a next-generation TKI that is relatively selective for FLT3. It was tested in a dose-escalation phase I trial in r/r
FLT3-ITD-positive AML patients [
34]. Here, monotherapy with the substance yielded a CR of 37.5%. In a phase III randomized trial, quizartinib monotherapy was compared with salvage chemotherapy in r/r
FLT3-ITD-positive AML [
35]. Salvage chemotherapy had to be preselected and included LDAC, FLAG-IDA, or MEC. OS was significantly longer in the investigational arm versus standard arm (6.2 versus 4.7 months) with manageable toxicities. Despite the positive phase III results, the FDA and EMA have not granted approval of the substance in r/r
FLT3-ITD-positive AML patients. Crenolanib, another next-generation TKI with promising results in a phase II trial, is currently also studied in a phase III trial for r/r FLT3-mutated AML (NCT03250338). In summary, next-generation TKIs with specific inhibitory effects for mutated FLT3 are promising in r/r AML. While midostaurin has received approval for FLT3-mutated AML in first line, gilteritinib is now approved for r/r FLT3-mutated AML by the FDA and EMA. It will be interesting to await the results of combination therapy, e.g., gilteritinib with venetoclax, in r/r FLT3-mutated AML (NCT03625505).