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IDH Inhibitor Olutasidenib Active With or Without Azacitidine in IDH1-Mutated AML

January 18, 2023

February 2023

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Treatment with olutasidenib led to durable remission and mutation clearance in patients with relapsed or refractory (R/R) IDH1-mutated acute myeloid leukemia (AML) with or without azacitidine, according to results of a phase I/II study conducted by Justin M. Watts, MD, of University of Miami Sylvester Comprehensive Cancer Center, and colleagues.

Olutasidenib is a potent, selective, small-molecule inhibitor of mutant IDH1. The multicenter, open-label study examined the safety and efficacy of olutasidenib in 78 adult patients with IDH1-mutated AML or intermediate-, high-, or very high-risk myelodysplastic syndromes (MDS), with no minimum bone marrow blast count for MDS. Olutasidenib was given orally in doses of 150 mg once daily, 150 mg twice daily, and 300 mg once daily. Forty-six patients received olutasidenib in combination with azacitidine, which was given at 75 mg/m2 either subcutaneously or intravenously for seven days and 21 days off. Results of the study were published in Lancet Haematology.

Among patients with R/R AML, responses occurred in 41% of patients receiving monotherapy and 46% receiving combination therapy. Median overall survival for patients with R/R disease was 8.7 months with monotherapy and 12.1 months with combination therapy.

Response rates were higher in the 17 patients with treatment-naïve disease: 25% of these patients (n=1/4) responded to monotherapy and 77% (n=10/13) responded to combination therapy.

“These results, when taken together with the established benefit of the venetoclax–azacitidine combination in treatment-naïve [AML], provide a strong rationale for future evaluation of either sequential or triplet therapy in this setting,” the researchers wrote.

For MDS, the overall response rate was 33% (2 of 6 patients) in the monotherapy group and 86% (5 of 7 patients) in the combination group. The researchers wrote that these data were the first “evaluation of an IDH1 inhibitor with azacitidine in patients with [MDS], and the first evaluation showing clinically significant activity of IDH inhibitor monotherapy in [MDS].”

No dose-limiting toxicities were reported, and no deaths were considered study-drug related. The recommended phase II dose was 150 mg twice per day.

The most commonly occurring grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (28%), febrile neutropenia (22%), and anemia (22%). With combination therapy, the most common were thrombocytopenia (41%), febrile neutropenia (28%), neutropenia (28%), and anemia (20%). Differentiation syndrome occurred in 13% of patients in both arms.

According to the researchers, this phase I/II study was limited by its open-label design, which could have resulted in selection bias.

“More specifically, the activity of combination therapy might consequently appear to be more encouraging than that of monotherapy if healthier or younger patients were allocated to treatment with olutasidenib and azacitidine, instead of olutasidenib alone,” the researchers wrote.

A subsequent phase II study led to the approval of olutasidenib by the U.S. Food and Drug Administration (FDA).

“The pivotal phase II cohort of olutasidenib monotherapy in IDH1-mutant [R/R] AML demonstrated a 35% complete remission (CR)/CR with partial hematologic recovery (CRh) rate and a 25.9-month median duration of CR/CRh, leading to its recent FDA approval,” Dr. Watts said.

In December 2022, the FDA approved olutasidenib for adults with R/R AML with a susceptible IDH1 mutation as detected by the Abbott RealTime IDH1 Assay. The recommended olutasidenib dose is 150 mg taken orally twice daily on an empty stomach.2

Any conflicts of interest declared by the authors can be found in the original article.


  1. Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial [published online, 2022 Nov 9]. Lancet Haematol. doi: 10.1016/S2352-3026(22)00292-7.
  2. U.S. Food & Drug Administration. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. December 1, 2022. Accessed December 16, 2022.




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