TY - JOUR
T1 - Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib
AU - Smith, Catherine C.
AU - Levis, Mark J.
AU - Perl, Alexander E.
AU - Hill, Jason E.
AU - Rosales, Matt
AU - Bahceci, Erkut
N1 - Funding Information:
This study was sponsored by Astellas Pharma, Inc. Medical writing support for this manuscript was provided by Kalpana Vijayan, Cheryl Casterline, MA, and Elizabeth Hermans of Peloton Advantage, LLC, an OPEN Health Company (Parsippany, NJ) and was supported by the study sponsor.
Funding Information:
Conflict-of-interest disclosure: C.C.S. reports research funding from AbbVie, Revolution Medicines; clinical trial funding from Cel-gene, FujiFilm; advisory board consulting fees from Astellas, Daiichi Sankyo, and Genentech; and stock ownership in Ligacept, LLC. M.J.L. reports grants from Astellas Pharma, Inc. and FujiFilm; honoraria from Amgen, AbbVie, Astellas Pharma, Inc., Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Menarini, and Takeda. A.E.P. reports grants, personal fees, and nonfinancial support from Astellas, during the conduct of the study; grants, personal fees, and nonfinancial support from Daiichi Sankyo, grants and personal fees from AbbVie and Actinium Pharmaceuticals; personal fees from Agios, Loxo, LLS/Beat AML, and Forma; nonfinancial support from Arog; personal fees and nonfinancial support from New Link Genetics, Novar-tis, Takeda, Jazz; and grants from Bayer and Biomed Valley Discoveries, outside the submitted work. J.E.H. and M.R. are employees of Astellas. E.B. was an employee of Astellas and received travel reimbursement as part of his employment.
Publisher Copyright:
© 2022 by The American Society of Hematology.
PY - 2022/4/12
Y1 - 2022/4/12
N2 - 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.
AB - 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.
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U2 - 10.1182/bloodadvances.2021006489
DO - 10.1182/bloodadvances.2021006489
M3 - Article
C2 - 35130342
AN - SCOPUS:85128329675
SN - 2473-9529
VL - 6
SP - 2144
EP - 2155
JO - Blood advances
JF - Blood advances
IS - 7
ER -