Olutasidenib and Azacitidine Show Efficacy and Durability for Treatment of R/R mIDH1 Acute Myeloid Leukemia

Combination therapy of olutasidenib and azacitidine demonstrated durability and safety for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with mutations in the isocitrate dehydrogenase 1 (mIDH1) gene, according to results from a phase 1/2 trial published in the Journal of Hematology & Oncology.

Olutasidenib has shown efficacy as a monotherapy for the treatment of R/R AML among patients with mutations in the mIDH1 gene.  Researchers analyzed results from previous phases evaluating the efficacy of olutasidenib with standard therapy, azacitidine for patients with R/R mIDH1 AML.

Enrolled patients with R/R mIDH1 AML were treated with combination olutasidenib and azacitidine therapy, in both phases. The 67 patients were stratified by history of prior therapies including patients previously treated with a hypomethylating agent or IDHI1 inhibitor, patients never treated with a hypomethylating agent, and patients treated with a IDHI1 inhibitor only.

Prior to the start of the study, hypomethylating agents were received by 40% of patients, IDHI1 inhibitor therapy was received by 31%, and 6% of patients previously received venetoclax therapy. Cytogenetic risk was poor in 18% of patients and 48% had intermediate risk. Patients who received combination olutasidenib and azacitidine had an overall response rate (ORR) of 51% (95% confidence interval [CI], 38 to 63), with a median response time of 2 months (range, 0.9 to 7.6). A complete response (CR) rate of 27% (95% CI, 18.7 to 19.3) was found with a median response time of 3 months (range, 1 to 7.6). The overall survival (OS) was 12.9 months (95% CI, 8.7-19.3).

Among patients who were initially treated with olutasidenib before combination therapy, the OS was higher than in patients who received combination therapy alone (7.5 months; 95% CI, 2.5 to 13.8 vs 18.1 months; 95% CI, 9.5 to 24.2). Similarly, patients who had prior exposure to hypomethylating agent therapy had better OS compared to patients only receiving combination olutasidenib and azacitidine (9.5 months; 95% CI, 3 to 12.2 vs 18.1 months; 95% CI, 9.3 to 30.6). Exposure to hypomethylating agent therapy was shown to have an increased CR (30%) and a median response time of 5.1 months (95% CI, 1.7 to not reached).

Additional analysis of patients who were transfusion dependent at enrollment found transfusion independence from red blood cells (29%) and platelets (33%) at 56 days post initial treatment.

In terms of safety, 97% of patients experience at least 1 adverse event (grade 4 or lower), of which 69% where treatment related.  Serious adverse events were reported in 70% of patients and 6% of patients discontinued treatment due to treatment-emergent adverse events. The most common adverse events were decreased levels of red blood cells (25%), neutrophil count (24%), and platelet counts (37%).

“To our knowledge this is the first study reporting the efficacy and safety of combination therapy with an mIDH1 inhibitor and HMA (hypomethylating agent) in the R/R AML setting,” the researchers concluded, “The observed efficacy is clinically meaningful and represents a new molecularly targeted therapeutic option for a patient population that has a poor prognosis and limited treatment options.”

Source:

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. Journal of Hematology & Oncology. Published online January 16, 2025. doi: 10.1186/s13045-024-01657-z