Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib

Abstract

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin-spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Graphical abstract

Figure 1.

Response rates across gene subgroups. (A) Rates of CR/CRh. (B) Rates of CR/CRh in patients eligible for high-intensity chemotherapy. ITT, intention-to-treat.

Figure 2.

Overall survival by molecular risk and comutated gene categories. (A) Intention-to-treat population. (B) Patients eligible for high-intensity chemotherapy. (C) Dual comutated DNMT3A and NPM1: patients eligible for high-intensity chemotherapy regimens. NE, not estimable.

Figure 3.

Overall survival by FLT3-ITD length at baseline. (A) Impact of FLT3-ITD length relative to median value: ≤51 bp vs >51 bp. (B) Relative impact of FLT3-ITD length and multiple FLT3-ITD mutations in the gilteritinib arm. (C) Relative impact of FLT3-ITD length and multiple FLT3-ITD mutations in the salvage chemotherapy arm.

Figure 4.

Mutations detected at baseline and at relapse in patients who relapsed on gilteritinib.

Figure 5.

Mutation profile of patients who relapsed on gilteritinib therapy. (A) New mutations at relapse. (B) New Ras/MAPK gene mutations at relapse. (C) New FLT3 mutations at relapse. Analyses were restricted to patients who had blood or bone marrow samples available at both baseline and at relapse. ^†Some patients had mutations in more than 1 Ras/MAPK pathway gene. ^‡One patient acquired a FLT3 F691L gatekeeper mutation as well as a JMD point mutation at relapse.