Gilteritinib Superior to Standard Chemotherapy in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Treatment with the oral FLT3/AXL inhibitor gilteritinib led to longer overall survival (OS) in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML), compared with standard chemotherapy, according to results from the phase III ADMIRAL trial presented at the 2019 American Association for Cancer Research Annual Meeting. Lead author Alexander Perl, MD, from Perelman School of Medicine at the University of Pennsylvania, presented the findings.

However, while gilteritinib was associated with high response and survival, most participants were not considered cured and long-term survival was poor in both arms, Dr. Perl told ASH Clinical News.

The U.S. Food and Drug Administration (FDA) approved gilteritinib in November 2018 based on interim safety and efficacy data from the ADMIRAL trial. In this analysis, Dr. Perl shared results from the final analysis of ADMIRAL, which enrolled individuals with clinically confirmed FLT3-mutated AML who had an untreated first relapse or whose disease was refractory to induction chemotherapy. Patients who had previously taken FLT3 inhibitors other than midostaurin or sorafenib were excluded from the analysis.

A total of 371 patients (median age = 62 years; range = 19-85 years) were randomized 2:1 to receive either:

  • gilteritinib administered in continuous 28-day cycles of 120 mg/day (n=247)
  • standard salvage chemotherapy (low-dose cytarabine, azacitidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin) (n=124)

Most patients (60.6%) had relapsed AML and 39.4% had refractory AML. Baseline FLT3 mutations included:

  • FLT3-ITD (88.4%)
  • FLT3-TKD (8.4%)
  • both FLT3-ITD and FLT3-TKD (1.9%)
  • unconfirmed (1.3%)

In the gilteritinib-treated group, patients had significantly longer OS compared with the standard treatment group: 9.3 months versus 5.6 months (hazard ratio [HR] = 0.637; p=0.0007). One-year survival rates for gilteritinib and chemotherapygroups were 37.1% and 16.7% respectively, although p values for the comparison were not reported. Median event-free survival had a trend toward improvement with gilteritinib: 2.8 months versus 0.7 months (HR=0.793; p=0.083).

More patients in the gilteritinib group achieved a complete remission/complete remission with partial hematologic recovery (CR/CRh): 34.0% vs. 15.3% in the chemotherapy group (p=0.0001).

The most frequently reported adverse events (AEs) across both treatment groups included:

  • febrile neutropenia (43.7%)
  • anemia (43.4%)
  • pyrexia (38.6%)

Grade ≥3 AEs associated with gilteritinib included anemia (19.5%), febrile neutropenia (15.4%), and thrombocytopenia (12.2%). The rate of serious treatment-emergent AEs per patient-year appeared lower with gilteritinib than chemotherapy (7.1% vs. 9.2%; p value not reported).

When asked about the study’s limitations, Dr. Perl noted that “we enrolled relatively few patients with FLT3-TKD mutations, which limited our ability to compare its efficacy in this subgroup with chemotherapy. Although gilteritinib had comparable remission rates and OS in FLT3-ITD and FLT3-TKD groups, the small sample size limited us from robustly demonstrating survival benefits for the FLT3-TKD subgroup.”

The standard frontline treatment for FLT3-mutated AML also shifted during enrollment for ADMIRAL, with the FDA approval of the FLT3 inhibitor midostaurin in April 2017. Some patients may have received prior FLT3-targeting therapy, which could potentially confound the results.

“Our biggest priority in the field is to optimize frontline therapy to prevent, rather than treat, relapsed/refractory AML,” Dr. Perl concluded. “To this end, trials of gilteritinib as part of induction, consolidation, and maintenance therapy for AML have been initiated. We hope that this will change the natural history of the disease and improve cure rate.”

The authors report relationships with Astellas, which sponsored the trial.


Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the phase III ADMIRAL trial. Abstract #CT184. Presented at the American Association for Cancer Research Annual