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Adding ivosidenib to azacitidine improves clinical outcomes in untreated, IDH-mutation positive AML patients who are unfit for intensive chemotherapy

Results of the phase III randomized controlled AGILE trial show that the combination of ivosidenib and azacitidine significantly prolongs the overall and event-free survival of patients with previously untreated acute myeloid leukemia (AML) harboring a mutation in the IDH1 gene, who are ineligible for intensive induction chemotherapy. As such, this trial identifies IVO+AZA as a potential new standard of care for this difficult-to-treat AML population.

Somatic mutations in metabolic enzyme isocitrate dehydrogenase 1 (IDH1) occur in 6–10% of patients with AML and are associated with a poor prognosis. Ivosidenib is an oral, potent inhibitor of mutant (m) IDH1 and is already FDA-approved for adults with relapsed/refractory mIDH1 AML and for elderly (≥75 years) mIDH1 AML patients or patients with comorbidities precluding the use of intensive induction chemotherapy (IC). Previously reported results of a phase Ib study including 23 newly diagnosed mIDH1 AML patients showed an encouraging clinical activity and a manageable safety profile for a combination of ivosidenib and azacitidine (IVO+AZA). These findings formed the basis for the randomized, phase III AGILE study in which IVO+AZA was compared to AZA plus placebo (PBO+AZA) in the treatment of newly diagnosed AML patients who are ineligible for intensive IC.

Study design

In AGILE, untreated AML patients with a centrally confirmed mIDH1 status who were not eligible for IC and had an ECOG 0-2 were randomly assigned to receive IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA). The primary endpoint of the study consisted of event-free survival defined as the time from randomization until treatment failure (i.e., failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause). Key secondary study objectives included the CR rate, overall survival (OS), the rate of CR + CR with partial hematologic recovery, and the objective response rate (ORR). At data cut off for this analysis, 146 patients had been randomized in the study. In May 2021 the IDMC recommended to halt study enrollment based on a noted difference in clinical importance between the treatment groups, not related to safety.


Baseline disease and patient characteristics were well balanced between the two study groups, with a median age of 76 years. About one third of patients in the study had an ECOG performance status of 2 and about a quarter had poor risk cytogenetics. Finally, three quarters of patients had de novo AML across the two treatment arms.

The EFS was significantly in favor of the IVO+AZA arm in the intent-to treat population with a hazard ratio (HR) of 0.33 (95%CI: 0.16, 0.69; p= 0.0011). This EFS benefit was consistent across subgroups, irrespective of the de novo status, baseline ECOG performance status, cytogenetic risk, WHO classification, baseline white blood cell count and the baseline percentage of bone marrow blasts. Also the OS was significantly in favor of IVO+AZA with a median of 24 months as compared to 7.9 months with PBO+AZA (HR[95%CI]: 0.44[0.27-0.73]; p= 0.0005). The CR rate obtained with IVO+AZA was reported at 47.2% while this was only 14.9% with PBO+AZA (p< 0.0001). The median time to CR was 4.3 months with IVO+AZA as compared to 3.8 months with PBO+AZA. The CR+CRh rate was 52.8% vs. 17.6% with IVO+AZA and PBO+AZA, respectively. The CR rate by 24 weeks for IVO+AZA vs. PBO+AZA were 37.5% and 10.8%, respectively.

Interestingly, IVO-AZA was also superior to PBO+AZA in terms of health-related quality of life, with clinically meaningful improvements in global health status and fatigue subscales over time for patients treated with IVO+AZA. Common all-grade adverse events (AEs) occurring in >20% of patients receiving IVO+AZA vs. PBO+AZA consisted of nausea (42.3% vs. 38.4%), vomiting (40.8% vs. 26.0%), diarrhea (35.2% vs. 35.6%), pyrexia (33.8% vs. 39.7%), anemia (31.0% vs. 28.8%), febrile neutropenia (28.2% vs. 34.2%), thrombocytopenia (28.2% vs. 20.5%), constipation (26.8% vs. 52.1%), and pneumonia (23.9% vs. 31.5%). Overall, 93.0% of patients treated with IVO+AZA experienced a grade ≥ 3 AE (vs. 94.5% with PBO+AZA). Common grade ≥3 AEs in patients receiving IVO+AZA vs. PBO+AZA included febrile neutropenia (28.2% vs. 34.2%), anemia (25.4% vs. 26.0%), thrombocytopenia (23.9% vs. 20.5%), and pneumonia (22.5% vs. 28.8%). The frequency of all-grade differentiation syndrome (DS) was 14.1% with IVO+AZA as compared to 8.2% with PBO+AZA (grade ≥3 DS: 4.2% vs. 4.1%).


IVO+AZA significantly prolongs the EFS and OS and improves the clinical response rate compared to PBO+AZA in patients with IC-ineligible, newly diagnosed mIDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. As such, these data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population.


Montesinos P, et al. AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. Presented at ASH 2021; Abstract 697.

Speaker Hartmut Döhner

Hartmut Döhner

Hartmut Döhner, MD, Ulm University Hospital, Ulm, Germany


See: Keyslides


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