Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Perl AE ，Larson RA ，Podoltsev NA ，Strickland S ，Wang ES ，Atallah E ，Schiller GJ ，Martinelli G ，Neubauer A ，Sierra J ，Montesinos P ，Récher C ，Yoon SS ，Hosono N ，Onozawa M ，Chiba S ，Kim HJ ，Hasabou N ，Lu Q ，Tiu R ，Levis MJ ... -  《-》

Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Perl AE ，Larson RA ，Podoltsev NA ，Strickland S ，Wang ES ，Atallah E ，Schiller GJ ，Martinelli G ，Neubauer A ，Sierra J ，Montesinos P ，Recher C ，Yoon SS ，Maeda Y ，Hosono N ，Onozawa M ，Kato T ，Kim HJ ，Hasabou N ，Nuthethi R ，Tiu R ，Levis MJ ... -  《-》

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Perl AE ，Martinelli G ，Cortes JE ，Neubauer A ，Berman E ，Paolini S ，Montesinos P ，Baer MR ，Larson RA ，Ustun C ，Fabbiano F ，Erba HP ，Di Stasi A ，Stuart R ，Olin R ，Kasner M ，Ciceri F ，Chou WC ，Podoltsev N ，Recher C ，Yokoyama H ，Hosono N ，Yoon SS ，Lee JH ，Pardee T ，Fathi AT ，Liu C ，Hasabou N ，Liu X ，Bahceci E ，Levis MJ ... -  《-》

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

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.

Smith CC ，Levis MJ ，Perl AE ，Hill JE ，Rosales M ，Bahceci E ... -  《-》

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Hosono N ，Yokoyama H ，Aotsuka N ，Ando K ，Iida H ，Ishikawa T ，Usuki K ，Onozawa M ，Kizaki M ，Kubo K ，Kuroda J ，Kobayashi Y ，Shimizu T ，Chiba S ，Nara M ，Hata T ，Hidaka M ，Fujiwara SI ，Maeda Y ，Morita Y ，Kusano M ，Lu Q ，Miyawaki S ，Berrak E ，Hasabou N ，Naoe T ... -  《-》