Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia

N Engl J Med. 2022 Apr 21;386(16):1519-1531. doi: 10.1056/NEJMoa2117344.


Background: The combination of ivosidenib - an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) - and azacitidine showed encouraging clinical activity in a phase 1b trial involving patients with newly diagnosed IDH1-mutated acute myeloid leukemia.

Methods: In this phase 3 trial, we randomly assigned patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were ineligible for intensive induction chemotherapy to receive oral ivosidenib (500 mg once daily) and subcutaneous or intravenous azacitidine (75 mg per square meter of body-surface area for 7 days in 28-day cycles) or to receive matched placebo and azacitidine. The primary end point was event-free survival, defined as the time from randomization until treatment failure (i.e., the patient did not have complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first.

Results: The intention-to-treat population included 146 patients: 72 in the ivosidenib-and-azacitidine group and 74 in the placebo-and-azacitidine group. At a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio for treatment failure, relapse from remission, or death, 0.33; 95% confidence interval [CI], 0.16 to 0.69; P = 0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib-and-azacitidine group and 12% in the placebo-and-azacitidine group. The median overall survival was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (hazard ratio for death, 0.44; 95% CI, 0.27 to 0.73; P = 0.001). Common adverse events of grade 3 or higher included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine) and neutropenia (27% and 16%, respectively); the incidence of bleeding events of any grade was 41% and 29%, respectively. The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine. Differentiation syndrome of any grade occurred in 14% of the patients receiving ivosidenib and azacitidine and 8% of those receiving placebo and azacitidine.

Conclusions: Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population. Febrile neutropenia and infections were less frequent in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib-and-azacitidine group. (Funded by Agios Pharmaceuticals and Servier Pharmaceuticals; AGILE ClinicalTrials.gov number, NCT03173248.).

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / adverse effects
  • Antineoplastic Agents* / therapeutic use
  • Azacitidine* / administration & dosage
  • Azacitidine* / adverse effects
  • Azacitidine* / therapeutic use
  • Febrile Neutropenia / chemically induced
  • Glycine / analogs & derivatives
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukopenia / chemically induced
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / therapeutic use
  • Recurrence


  • Antineoplastic Agents
  • Pyridines
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Azacitidine
  • ivosidenib
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT03173248