Journal Article

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

Ferrell, P. Brent, de Botton, Stéphane, Yee, Karen, Wang, Eunice S., Tian, Hua, Roboz, Gail J., Baer, Maria R., Yang, Jay, Mims, Alice, Curti, Antonio, Cortes, Jorge E., Jonas, Brian A., Schiller, Gary J., Blum, William G., Watts, Justin M., Montesinos, Pau, Sheppard, Aaron

2025

Overview

Background Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) m IDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Methods Adult patients with m IDH1 R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Results Sixty-seven patients with R/R m IDH1 R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Conclusions Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with m IDH1 AML who may benefit from a targeted therapy. Trial registration NCT02719574.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute myeloid leukemia / Adult / Adverse events / Aged / Aged, 80 and over / AML / Analysis / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Azacitidine - administration & dosage / Azacitidine - adverse effects / Cancer Research / Clinical trials / Combination therapy / Cytogenetics / Diseases / Drug dosages / Erythrocytes / Female / Hematology / Hematopoietic stem cells / Humans / Hypomethylating agent / Isocitrate Dehydrogenase - antagonists & inhibitors / Isocitrate Dehydrogenase - genetics / Isocitrate dehydrogenase-1 / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukocytes (neutrophilic) / Male / Medical prognosis / Medicine / Medicine & Public Health / Middle Aged / Mutant IDH1 inhibitor / Mutation / Oncology / Patients / Platelets / Pyridines - administration & dosage / Pyridines - adverse effects / Quinolines / Refractory / Relapse / Relapsed / Remission / Remission (Medicine) / Remission Induction / Stem cell transplantation / Transplantation