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ADMIRAL Trial: Genetic Mutations in Patients With Resistant AML

By: Lauren Harrison, MS
Posted: Sunday, March 1, 2020

Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations were the most common mutations in patients with acute myeloid leukemia (AML) who have a mutated FLT3 gene and experienced relapse on gilteritinib therapy in the ADMIRAL trial. Catherine C. Smith, MD, of the University of California, San Francisco, presented these study findings on behalf of her colleagues at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 14) and published them in the journal Blood.

A total of 75 of the 247 patients assigned to treatment with the oral FLT3 inhibitor in the ADMIRAL trial relapsed over the course of the study, and 40 of these patients had samples available for comparison. Most relapses occurred within the first 4 weeks after the last gilteritinib dose.

Researchers used blood or bone marrow samples to perform next-generation sequencing to identify other mutations that may have contributed to patient relapse. They used baseline samples to characterize other co-mutations as well. At the time of relapse, 27 patients (67.5%) who relapsed had new mutations in the Ras/MAPK pathway genes (18 patients), FLT3 (6 patients), WT1 (3 patients), IDH1 (1 patient), and GATA2 (1 patient).

Among the patients with new Ras/MAPK mutations, 61.1% had more than one new mutation at the time of relapse. NRAS was the most frequently mutated RAS/MAPK pathway gene (11 patients). In addition, 25 patients in this trial had Ras/MAPK pathway gene mutations at baseline (6.9%), but just 12% of these patients had more than one RAS/MAPK pathway mutation. A number of the patients who had Ras/MAPK mutations at baseline were able to achieve remission, and the rate of composite complete remission was 38.9% (complete permission or complete remission with incomplete hematologic/platelet recovery).

In total, six patients acquired new FLT3 mutations at relapse, with five of them acquiring an F691L gatekeeper mutation. Three patients acquired a WT1 mutation at relapse, and one of these patients also developed an F691 gatekeeper mutation. Acquisition of any these mutations was mutually exclusive.

Disclosure: For full disclosures of the study authors, visit ashpublications.org.



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