Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML

Autores de IIS La Fe

• Pau Montesinos Fernández

  Autor

Participantes ajenos a IIS La Fe

• Marchione, Dylan M.
• Recher, Christian
• Heuser, Michael
• Vives, Susana
• Zarzycka, Ewa
• Wang, Jianxiang
• Riva, Marta
• Calado, Rodrigo T.
• Schuh, Andre C.
• Yeh, Su-Peng
• Tron, Adriana E.
• Hui, Jianan
• Gianolio, Diego A.
• Choe, Sung
• Patel, Prapti
• De Botton, Stephane
• DiNardo, Courtney D.
• Dohner, Hartmut

Grupos

• Hematología y Hemoterapia

Abstract

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1(IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75). Median OS was significantly longer with ivosidenib (29.3 months; 95% confidence interval [CI], 13.2 to not reached) than with placebo (7.9 months; 95% CI, 4.1-11.3; hazard ratio, 0.42 [95% CI, 0.27-0.65]; P < .0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; P = .0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03173248.

© 2025 American Society of Hematology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords

• ACUTE MYELOID-LEUKEMIA; MEASURABLE RESIDUAL DISEASE; PROGNOSTIC-SIGNIFICANCE; VENETOCLAX; MUTATIONS