Olutasidenib and Azacitidine Combination Expands Options for mIDH1 Relapsed or Refractory AML

Durable remissions were shown in patients with high-risk, relapsed or refractory, IDH1-mutant acute myeloid leukemia (AML) treated with the experimental combination of olutasidenib and azacitidine in multiple studies.

“Olutasidenib plus azacitidine showed a notable overall response rate in 51% of patients, with a median overall survival of 12.9 months, a significant milestone in the treatment of relapsed/refractory AML using a targeted combination approach,” Justin M. Watts, MD, an oncologist in the Division of Hematology, Department of Medicine, at the University of Miami Hospital told Blood Cancers Today.

Findings come from pooled data from three cohorts of patients with relapsed or refractory IDH1-mutant AML treated in a phase II study and two cohorts of patients from a phase I study. All cohorts received the same dose of the combination, which consisted of olutasidenib, 150 mg, twice daily for 28-day cycles and azacitidine, 75 mg/m², daily for seven consecutive days in 28-day cycles. The analysis cohort included 67 patients who were treated at 32 sites across the United States and Canada and in Europe and Asia Pacific. Twenty of the patients were from the phase I study, and 47 were from the phase II study.

Results show that 21 of 67 patients achieved a complete response (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 31% (95% CI, 21%-44%). The median duration of CR/CRh was 14.7 months (95% CI, 4.6-not reached). CR only occurred in 27% of patients (95% CI, 17%-39%), with a 20.3-month median duration of CR (95% CI, 3.7-not reached).

“A subset of patients had a very durable response, and we are working to understand who these patients are that have the greatest benefit,” said Watts.

The subset analysis observed 51 patients with relapsed or refractory AML who had prior exposure to olutasidenib. In the subset, the CR/CRh rate was 37% (95% CI, 24%-52%), and the CR rate was 31% (95% CI, 19%-46%). The result was an overall response rate of 59% (95% CI, 44%-72%).

Treatment with the combination of olutasidenib and azacitidine also led to transfusion independence in some patients. In the overall study population, patients who achieved a CR/CRh had a 64% rate of transfusion independence, and those who were transfusion dependent at baseline had a 57% rate of transfusion independence after treatment.

According to Cortes et al, olutasidenib plus azacitidine has a well characterized and manageable safety profile. Any-grade treatment-emergent adverse events (TEAEs) occurred in 97% of patients, and grade 3/4 TEAEs occurred in 90%.

The most common any-grade hematologic AEs included decreased platelet count (39%), decreased red blood cell count (27%), and decreased neutrophil count (25%). The AEs were high grade in 37%, 25%, and 24% of patients, respectively. The most common nonhematologic AEs were nausea (52%), constipation (42%), and vomiting (40%); and these AEs were grade 3/4 in 4%, 4%, and 4% of patients, respectively.

This was the first study to evaluate the efficacy and safety of an IDH1 inhibitor and hypomethylating agent in the setting of relapsed or refractory AML. The efficacy observed was deemed clinically meaningful, positioning the combination of olutasidenib and azacitidine as a new option that is molecularly targeted to treat IDH1-mutant, relapsed or refractory AML.

“Multiple studies are currently examining the olutasidenib plus venetoclax and azacitidine triplet in the frontline setting, which may represent the future for many patients with IDH1-mutated AML,” Watts said.

 

Reference

Cortes JE, Roboz GJ, Baer MR, et al. Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial. J Hematol Oncol. 2025;18(1):7. doi: 10.1186/s13045-024-01657-z