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During an oral abstract session at the 25th European Hematology Association (EHA) Annual Congress, Catherine C. Smith presented abstract S147 on the emerging mutations at relapse in patients with FLT3-mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) who received gilteritinib therapy in the phase III ADMIRAL trial.1
There is often a poor prognosis for patients with R/R AML as they are unlikely to respond to salvage chemotherapy. FLT3 internal tandem duplication (ITD) mutations are associated with increased risk of relapse and poor survival. With the emergence of FLT3-targeted therapies, the treatment paradigm for these patients has shifted. Gilteritinib, a highly selective, second-generation FLT3 inhibitor was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a single agent based on the ADMIRAL phase III trial (NCT02421939). It has shown great promise in the R/R AML setting, demonstrating superior overall survival and deeper responses compared with salvage chemotherapy. However, secondary treatment-emergent mutations in the tyrosine kinase domain (TKD) can confer resistance to FLT3 inhibitor therapy. The aim of this study was to evaluate the emerging mutations in patients who relapsed on gilteritinib therapy in the ADMIRAL trial. 1
Figure 1. New gene mutations at relapse1
A The numbers of patients with each type of mutation. B The numbers of mutations of the Ras/MAPK pathway.
Figure 2. Comparison of Ras/MAPK gene mutations per patient at baseline and relapse1
A The numbers of Ras/MAPK pathway gene mutations per patient at baseline. B The numbers of new Ras/MAPK pathway gene mutations per patient at relapse.
The most common mutational events associated with gilteritinib resistance in patients with FLT3-mutated R/R AML in the ADMIRAL trial were mutations in Ras/MAPK pathway genes and FLT3 F691L mutations. The presence of Ras/MAPK pathway gene mutations at baseline did not preclude response to gilteritinib therapy as there were fewer mutations per patient at baseline than at relapse. The acquisition of Ras/MAPK pathway gene mutations at relapse is suggestive of reactivation of this pathway. The incidence of FLT3 F691L mutations was similar to those reported in patients with FLT3-mutated R/R AML who relapsed after gilteritinib treatment in the CHRYSALIS phase I/II study (NCT02014558).
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