ADMIRAL Study: Emerging Mutations in Gilteritinib-Treated Patients with Relapsed/Refractory AML

A study presented at the American Society of Hematology Annual Meeting and Exposition evaluated emerging mutations in patients with acute myeloid leukemia (AML) who relapsed while receiving gilteritinib therapy in the ADMIRAL study.

Study author Catherine C. Smith, MD, presented the findings in an oral abstract session on Saturday at the meeting, which is being held December 7-10, 2019, in Orlando, Florida.

The emergence of more targeted therapies has shifted the treatment paradigm for patients with AML. Gilteritinib, a novel, potent oral FLT3 inhibitor, showed significant improvement in overall survival and higher remission rates compared with salvage chemotherapy in patients with FLT3-mutation-positive relapsed/refractory (R/R) AML in the phase 3 ADMIRAL study. However, as with other FLT3 inhibitors, patients often develop resistance after an initial response to gilteritinib, according to Dr Smith.

For the analysis, the authors used blood or bone marrow samples from 361 patients at baseline and for 40 patients who relapsed on gilteritinib treatment. Of the 371 patients in the study, 247 were assigned gilteritinib 120 mg per day. Seventy-five relapsed during the study. Most relapses occurred ≤4 weeks from the last gilteritinib dose, according to the data.

At relapse, 67.5% had new mutations, including mutations in Ras/MAPK pathway genes, FLT3, WT1, IDH1, and GATA2, whereas 32.5% of patients had no new mutations.

Of the 18 patients with Ras/MAPK pathway gene mutations at relapse, 61.1% had >1 mutation. The most frequently mutated Ras/MAPK pathway gene was NRAS.

Among all FLT3-mutation-positive patients analyzed for co-mutated genes at baseline, 6.9% had Ras/MAPK pathway gene mutations detected (gilteritinib, n=18; salvage chemotherapy, n=7; median VAF, 13% [range, 3.4%-50%]). Additionally, 12% of patients had >1 Ras/MAPK pathway gene mutation at baseline and 61.1% had >1 Ras/MAPK pathway gene mutations at relapse, according to the study.

Notably, the rate of complete remission (CR) with incomplete hematologic/platelet recovery was 38.9% and the rate of CR/CR with partial hematologic recovery was 27.8% among gilteritinib-treated patients who had Ras/MAPK pathway gene mutations at baseline. Six patients acquired new FLT3 mutations at relapse. Five of these 6 patients acquired an F691L gatekeeper mutation and 1 of these 5 patients also acquired a FLT3 juxtamembrane domain point mutation. Of the 3 patients who acquired a WT1 mutation at relapse, 1 also acquired a FLT3 F691L gatekeeper mutation.

Importantly, the acquisition of Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations at relapse was mutually exclusive, Smith added.

Overall, the study showed that Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations were the most common mutational events. However, the presence of a Ras/MAPK pathway gene mutation at baseline did not preclude response to gilteritinib therapy, possibly due to the presence of fewer mutations per patient at baseline than at relapse, according to Smith.

The frequency of emergent FLT3 F691 gatekeeper mutations at relapse in patients who received the ADMIRAL study dose was similar to that observed in patients who received 20- to 450-mg per day.

Reference

Smith CC, Levis MJ, Perl AE, et al. Emerging mutations at relapse in patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial. Presented at: ASH Annual Meeting and Exposition. Orlando, Florida. December 7, 2019. Abstract 14. https://ash.confex.com/ash/2019/webprogram/Paper122620.html