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Gilteritinib Outperforms Standard Chemotherapy in FLT3-Mutated AML, Regardless of Mutation Burden

December 30, 2021

According to an analysis from the phase III ADMIRAL trial, treatment with gilteritinib was associated with higher response rates and longer survival than chemotherapy alone in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). This clinical benefit was maintained regardless of comutations, according to study investigators. Lead author Alexander Perl, MD, shared these findings at the 24th Congress of the European Hematology Association.

"Once people relapse with FLT3-mutated AML, it can be very hard to cure them because they don't respond well to any subsequent chemotherapy," Dr. Perl told ASH Clinical News. "Today there is not an approved drug as a single agent to inhibit FLT3, and the only inhibitors approved are in the context of combination therapy where we don't know whether they're working because they are inhibiting FLT3 or because we're just treating patients with this mutation."

The ADMIRAL trial compared the safety and efficacy of gilteritinib with salvage chemotherapy in 371 patients (median age = 62 years; range = 19-85 years) with clinically confirmed FLT3-mutated AML or AML secondary to myelodysplastic syndromes. Patients who had previously taken FLT3 inhibitors other than midostaurin or sorafenib were excluded from the analyses.

Participants were randomized 2:1 to receive either:

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

At baseline, 61% of patients had relapsed AML , and 39% had refractory AML. The most commonly observed mutations were FLT3-ITD mutations (88.4%), followed by FLT3-TKD mutations (8.4%) and both FLT3-ITD and FLT3-TKD mutations (1.9%). The remaining 1.3% of patients had unconfirmed FLT3 mutations.

Overall survival (OS) was significantly longer in the gilteritinib-treated group compared with patients who were randomized to receive standard chemotherapy (9.3 months vs. 5.6 months, respectively; hazard ratio for death = 0.637; p=0.0007). Gilteritinib also was associated with significantly higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi), compared with standard chemotherapy (34.0% vs. 15.3%; p=0.0001).

"After adjustment for therapy duration, grade 3 or higher adverse events (AEs) were less frequent in the gilteritinib arm (7.1% vs. 9.2%)," Dr. Perl noted, though p values were not reported. The most common AEs in the gilteritinib arm included anemia (19.5%), febrile neutropenia (15.4%), and thrombocytopenia (12.2%).

Dr. Perl also reported findings from an analysis of comutations among 361 study participants who had blood and bone marrow DNA samples available for next-generation sequencing. The most commonly comutated genes were NPM1 (47.9%), DNMT3A (31.9%), DNMT3A/NPM1 (23.8%), and WT1 (18%). In addition, IDH1 or IDH2 comutations were present in 15.5% of patients.

The investigators found that, across all comutation subgroups, gilteritinib was associated with higher CR/CRi rates than the chemotherapy group. However, "relative to other comutated cohorts, patients with both NPM1 and DNMT3A comutations had the greatest survival benefit with gilteritinib," the investigators reported:

  • NPM1: 32.3% with gilteritinib vs. 12.1% with chemotherapy
  • DNMT3A: 37.3% vs. 12.5%
  • DNMT3A/NPM1: 40% vs. 9.7%
  • WT1: 35.6% vs. 5.0%
  • IDH1/IDH2: 31.6% vs. 16.7%

Median OS also appeared to be longer with gilteritinib regardless of mutation burden, Dr. Perl added. Among gilteritinib-treated patients with a high or low FLT3-ITD allelic ratio, median OS was 7.1 months and 10.6 months, respectively, compared with 4.3 months and 6.9 months in the salvage chemotherapy group (p values not reported). "In the salvage chemotherapy arm, the low FLT3-ITD allelic ratio cohort had a survival advantage when compared with the high FLT3-ITD allelic ratio cohort," he added.

Together, these results support the use of gilteritinib in this cohort of patients with relapsed/refractory, FLT3-mutated AML, irrespective of comutation status and FLT3-ITD allelic ratio, the authors concluded. However, the findings of this study are potentially limited by the small number of patients with FLT3-TKD mutations, suggesting the results may not be generalizable to that patient population, and by the number of analyses that were not prespecified.

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


Perl A, Martinelli G, Cortes J, 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 3 ADMIRAL trial. Abstract #S876. Presented at the 24th European Hematology Association Annual Congress, June 15, 2019; Amsterdam, The Netherlands.


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