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Single-agent gilteritinib improves response and survival in relapsed/refractory FLT3-mutated AML patients

The final results of the ADMIRAL trial were presented at EHA 2019. As a single-agent oral drug gilteritinib demonstrated to be superior to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed/refractory (R/R) AML, both on overall survival and response rates. The toxicity of gilteritinib compared favourably to chemotherapy during treatment.


Patients with R/R AML have poor response rates to salvage chemotherapy and short survival. In AML, activating FLT3 mutations occur in ~30% of patients. Several FLT3 inhibitors have been developed, among which midostaurin, which improves survival in combination with intensive chemotherapy in patients with newly diagnosed FLT3-mutated AML. Gilteritinib is a potent/selective oral inhibitor of fms-like tyrosine kinase 3 (FLT3). In phase I/II studies it demonstrated single-agent antileukemic activity in FLT3-mutated R/R AML patients at doses ≥80 mg/day.


The ADMIRAL trial was a global phase III randomised study. Adults with confirmed FLT3-mutated AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomised (2:1) to receive continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomisation selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Patients treated with a FLT3 inhibitor previously, other than midostaurin or sorafenib, were excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints included event-free survival (EFS) and CR rate; safety/tolerability was also examined.


A total of 371 patients were randomised: 247 to gilteritinib and 124 to SC (MEC: 25.7%; FLAG-IDA: 36.7%; LoDAC: 14.7%; AZA: 22.9%). The median age was 62 years (range: 19-85). Baseline FLT3 mutations were: FLT3-ITD: 88%; FLT3-TKD: 8%; both FLT3-ITD and FLT3-TKD: 2%; unconfirmed: 1%. Overall, 39% of patients had refractory AML and 61% had relapsed AML. Patients randomised to gilteritinib had a significantly longer OS (9.3 months) compared to patients treated with SC (5.6 months; HR 0.637; P=0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (P=0.0001); CR rates were 21.1% and 10.5% (2-sided P=0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P=0.0830). Subgroup analysis did not reveal differences in effect for specific mutation subgroups. The number of patients with FLT3-TKD mutations only was too small for statistically robust conclusions, though.

Common adverse events (AEs) in all randomised patients were febrile neutropenia (43.7%), anaemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anaemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment-emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%).


The single-agent oral gilteritinib improves responses and survival compared with parenteral salvage chemotherapy in patients with FLT3-mutated R/R AML. The drug was associated with lower toxicity during the first 30 days of treatment, facilitating outpatient administration of the drug. The results presented demonstrate that gilteritinib could serve as a new standard treatment option for salvage therapy for FLT3-mutated R/R AML patients.


Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia: results from the phase 3 ADMIRAL trial. Presented at EHA 2019; abstract S876.

Speaker Alexander Perl


Alexander E. Perl, MD, MSc, University of Pennsylvania, Philadelphia, PA, USA


See: Keyslides


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