Somatic mutations in IDH1 occur in 6 to 16 percent of patients with acute myeloid leukemia (AML) and cause the production of D-2-hydroxyglutarate, which contributes to the development of AML by altering epigenetic regulation and metabolism.1 Ivosidenib is a small molecule inhibitor of mutant IDH1 that is FDA-approved as a single agent for relapsed or refractory IDH1-mutated AML as well as for newly diagnosed IDH1-mutated AML in patients who are 75 years or older, or who are otherwise ineligible for intensive induction chemotherapy owing to comorbidities.2 A recent phase Ib study of ivosidenib in combination with azacitidine showed that this combination is well-tolerated, with promising rates of response.3
The results of the phase III double-blind AGILE trial, which randomized patients with previously untreated AML with an IDH1 mutation to either ivosidenib with azacitidine (ivo/aza) or placebo with azacitidine (placebo/aza), were recently reported by Dr. Pau Montesinos and colleagues. Patients included in the study had a centrally confirmed IDH1 mutation and were ineligible for intensive induction chemotherapy based on age 75 years or older, or because of comorbidities as defined by the protocol. Patients who had previously received a hypomethylating agent (HMA) or an IDH1 inhibitor for prior myelodysplastic syndrome were excluded. The primary end point was event-free survival (EFS; time to treatment failure, relapse, or death). Secondary end points included response rates, overall survival (OS), safety, and quality-of-life measures.
Participants were enrolled from March 2018 until May 2021, when accrual to the study was stopped early because the data monitoring committee noted a difference in survival favoring ivo/aza. A total of 146 subjects were randomized, with 72 patients assigned to ivo/aza and 74 assigned to placebo/aza. Patient characteristics were comparable between the two groups. EFS was improved in the ivo/aza group compared to placebo/aza, with a hazard ratio of 0.33 (95% CI, 0.16-0.69; p=0.002) after a median follow-up of 12.4 months. The median OS was also longer in the ivo/aza group (24.0 months) than the placebo/aza group (7.9 months; hazard ratio for death, 0.44; 95% CI, 0.27-0.73; p=0.001). Complete remission rates were higher in the ivo/aza group as well. Although the time to response was similar in the two groups (4.3 months in the ivo/aza group and 3.8 months in the placebo/aza group), among patients who achieved a complete remission, more patients remained in remission at 12 months in the ivo/aza group (88%) than in the aza/placebo group (36%).
Regarding safety, patients in the ivo/aza group had lower rates of neutropenic fever (28% vs. 34%) and infection (28% vs. 49%), but higher rates of neutropenia (27% vs. 16%) and bleeding (41% vs. 29%) compared to the aza/placebo group. Differentiation syndrome was observed in 14 percent of ivo/aza–treated patients.
In Brief
Ivo/aza improves EFS, OS, and remission rates compared to placebo/aza in patients with newly diagnosed IDH1-mutated AML who are unfit for intensive induction chemotherapy. Of note, venetoclax in combination with azacitadine was approved by the U.S. Food and Drug Administration in 2018 and has also been shown to improve OS and remission rates compared to single-agent azacitidine.4 This study was conducted globally, where access to venetoclax may not have been possible. Cross-trial comparisons are difficult; multiple questions remain therefore, regarding the optimal treatment for a newly diagnosed unfit patient with AML with an IDH1 mutation. What is the optimal way to sequence available therapies in IDH1-mutated AML (i.e., should a patient receive venetoclax+HMA or ivosidenib+HMA as frontline therapy)? Will a triplet regimen of ivosidenib+venetoclax+HMA lead to even better outcomes, or will this increase toxicity? Several ongoing and planned studies may help to answer some of these questions.
Competing Interests
Dr. Hayden and Dr. McMahon indicated no relevant conflicts of interest.
