As reported in The New England Journal of Medicine by Perl et al, the phase III ADMIRAL trial showed improved overall survival with the oral FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib vs salvage chemotherapy in patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML).

Gilteritinib was approved by the U.S. Food and Drug Administration in this setting in November 2018 on the basis of an interim analysis of response rate and duration of response in the gilteritinib arm of ADMIRAL. 

“Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.”

— Perl et al

Tweet this quote

Study Details

The open-label trial included 371 patients from 107 sites in 14 countries, and they were enrolled between October 2015 and February 2018. Patients were randomly assigned 2:1 to receive gilteritinib at 120 mg/d (n = 247) or investigator’s choice of salvage chemotherapy (n = 124), with treatments being given in 28-day cycles. Chemotherapy was selected prior to randomization and could consist of either mitoxantrone/etoposide/cytarabine (MEC); fludarabine/cytarabine/ granulocyte colony-stimulating factor/idarubicin (FLAG-IDA); low-dose cytarabine; or azacitidine.

MEC and FLAG-IDA were considered high-intensity regimens. Patients receiving high-intensity chemotherapy were assessed for response on or after day 15 to determine the need for a second induction cycle. Patients receiving gilteritinib or low-intensity chemotherapy continued treatment until lack of clinical benefit, unacceptable toxicity, or other protocol-specified reasons for discontinuation.

The two primary endpoints were overall survival and percentage of patients with complete remission with full or partial hematologic recovery in the intention-to-treat population. The current report presents the final analysis of the trial, with event cutoff occurring in September 2018.

Overall, 39.4% of patients had primary refractory disease, 60.6% had relapsed disease, and 73% had intermediate cytogenetic risk. Salvage chemotherapy consisted of high-intensity regimens in 60% of both treatment groups.

Overall Survival and Complete Remission

The median duration of follow-up for overall survival in the final analysis was 17.8 months. Median overall survival was 9.3 months in the gilteritinib group vs 5.6 months in the chemotherapy group (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.49–0.83; P < .001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (HR for treatment failure or death = 0.79, 95% CI = 0.58–1.09).

Complete remission with full or partial hematologic recovery occurred in 34.0% vs 15.3% of patients (absolute 18.6% risk difference, 95% CI = 9.8%–27.4%), with complete remission with full recovery occurring in 21.1% vs 10.5% (absolute 10.6% risk difference, 95% CI 2.8%–18.4%). The median duration of complete remission with full or partial hematologic recovery was 11.0 months in the gilteritinib group.

Adverse Events

The median durations of exposure to gilteritinib and chemotherapy were 18 weeks and 4 weeks. The incidence of exposure-adjusted grade ≥ 3 adverse events was 19.34 events per patient-year in the gilteritinib group and 42.44 events per patient-year in the chemotherapy group.

The most common grade ≥ 3 adverse events in the gilteritinib group were febrile neutropenia (45.9% vs 36.7% in chemotherapy group), anemia (40.7% vs 30.3%), and thrombocytopenia (22.8% vs 16.5%). The incidence of exposure-adjusted serious adverse events was 7.11 per patient-year in the gilteritinib group and 9.24 per patient-year in the chemotherapy group. The most common serious adverse events considered to be related to gilteritinib treatment were febrile neutropenia (9.3%), increased alanine aminotransferase (4.5%), and increased aspartate aminotransferase (4.1%).

Drug-related adverse events led to discontinuation of gilteritinib in 11.0% of patients. Fatal infection occurred in 11.4% and 6.4% of patients. The most common fatal adverse events considered to be drug-related in the gilteritinib group were pneumonia (1.2%), large intestine perforation (0.8%), and septic shock (0.8%).

The investigators concluded, “Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.”

Disclosure: The study was funded by Astellas Pharma. For full disclosures of the study authors, visit nejm.org.