During the phase 3 ADMIRAL trial, the FLT3 inhibitor gilteritinib (Xospata) was compared with salvage chemotherapy and resulted in higher remission rates and prolonged overall survival in patients with FLT3-mutated relapsed/refractory (R/R) acute myeloid leukemia (AML). This was true even in the presence of additional mutations associated with AML. Some patients with FLT3 mutation–positive, R/R AML had resistance after initial response to gilteritinib, mediated by expansion of leukemic clones containing mutations in the RAS/MAPK pathway genes NRAS and KRAS.This study was designed to evaluate emerging mutations in patients who relapsed on gilteritinib therapy in the ADMIRAL trial.
Of the 371 patients enrolled in the ADMIRAL trial, 247 were assigned to receive gilteritinib 120 mg daily; 75 (30.5%) relapsed during the study. Most (96.0%) relapses occurred within 4 weeks from the last gilteritinib dose. Of these 75 relapsed patients, 40 had blood or bone marrow samples available at both baseline and relapse for comparison. These samples were analyzed using next-generation sequencing.
At relapse, 27 of 40 patients had new mutations. Many of these mutations occurred in RAS/MAPK pathway genes (N = 18), the most frequent of which was NRAS (N = 11). Additional RAS/MAPK genes included KRAS (N = 7), PTPN11 (N = 8), BRAF (N = 1), and CBL (N = 1). Mutations also occurred in FLT3 (N = 6), WT1 (N = 3), IDH1 (N = 1), and GATA2 (N = 1). No new mutations were found in 13 (32.5%) patients.
Of the 18 patients with RAS/MAPK pathway gene mutations at relapse, 11 (61.1%) had more than 1 new mutation at relapse (range, 2-6). Of the 361 FLT mutation–positive patients analyzed at baseline, RAS/MAPK pathway gene mutations were already present in 25 (6.9%), 18 (72%; 5% of total) of which were in the gilteritinib arm and 7 (28%; 1.9% of total) of which were in the salvage chemotherapy arm (median variant allele frequency, 13% [range, 3.4%->50%]). While 3 of these 25 patients (12.0%) had ≥1 RAS/MAPK pathway gene mutations at baseline, 11 (61.1%) had ≥1 RAS/MAPK pathway gene mutations at relapse.
Interestingly, 7 of 18 patients with RAS/MAPK pathway gene mutations at baseline achieved remission, resulting in a composite complete remission (complete remission [CR] or CR with incomplete hematologic recovery [CRh]) rate of 38.9%. The CR/CRh rate was 27.8% (5 of 18 patients).
Of the 6 patients who acquired a new FLT3 mutation, 5 acquired a G691L gatekeeper mutation, while 1 acquired an FLT3 point mutation affecting the juxtamembrane domain. Of the 3 patients who acquired a WT1 mutation, 1 also acquired the FLT3 F691L mutation. Interestingly, no patients acquired mutations in RAS/MAPK pathway genes and FLT3 at relapse.
In conclusion, 27 patients with FLT mutation–positive R/R AML that relapsed on gilteritinib therapy acquired new mutations that were not present at baseline. The most common mutations occurred in RAS/MAPK pathway genes and FLT3. Patients with mutations in RAS/MAPK pathway genes at baseline were still able to experience benefit from gilteritinib therapy, but this may have been due to having fewer mutations at baseline. Additional research into the role of RAS/MAPK signaling in patients with FLT mutation–positive R/R AML receiving gilteritinib is worth consideration.
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: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S147.
