Combination of Olutasidenib and Azacitidine Induces Durable Complete Remissions in mIDH1 Acute Myeloid Leukemia: A Multicohort Open-Label Phase 1/2 Trial
Authors: Cortes Jorge E. , Roboz Gail J. , Watts Justin M. , Baer Maria R. , Jonas Brian A. , Schiller Gary J. , Yee Karen , Ferrell Brent , Yang Jay , Wang Eunice S. , Blum William , Mims Alice 
Published: December 2024

Introduction: Treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains a significant challenge as standard chemotherapies have limited efficacy and may be contraindicated in elderly or frail patients. Relapse and resistance to current therapies are common outcomes, and both quality and length of life decrease with successive lines of therapy. Hypomethylating agents (HMAs), such as azacitidine (AZA), are frequently used for both newly diagnosed and R/R AML, but have limited single-agent responses. Olutasidenib (OLU) is a potent, selective, oral, small molecule inhibitor of mutated IDH1 (mIDH1) and is FDA-approved for treatment of patients with mIDH1 R/R AML. A phase 1/2 registrational trial demonstrated that OLU monotherapy induced complete remission (CR) or CR with partial hematologic recovery (CRh) in 35% of patients with R/R mIDH1 AML for a median duration of 25.9 months. We present a pooled analysis of patients with R/R AML who received a combination of OLU and AZA from the registrational, phase 1/2 trial (clinicaltrials.gov NCT02719574).
Methods: Adult patients with R/R mIDH1R132 AML received twice daily 150 mg OLU (in continuous 28-day cycles) plus standard-of-care AZA (daily for 7 consecutive days, in 28-day cycles) and were evaluated for safety and response.
Results: Sixty-seven patients with R/R mIDH1R132 AML received combination OLU+AZA after a median 10.2 months since AML diagnosis; 43% were refractory and 57% relapsed to prior treatment. Median age was 66 years (range 28-82), and 54% were male. Baseline ECOG was 0-1 in 82%. Most (83%) patients had 2+ prior treatment regimens, including HMA in 40%, IDH1 inhibitor therapy in 31% (olutasidenib monotherapy in 24%), and hematopoietic stem cell transplant (HSCT) in 10%. Cytogenetic risk class was intermediate in 72%, poor in 18% and unknown in 10%. One to 3 co-mutations were identified in 58% of patients, 4-7 in 19%, with FLT3 in 19% and TP53 in 6%.
CR/CRh was achieved in 21/67 (31%; 95% CI, 21-44) patients, and median duration of CR/CRh was 15 months (range 0.4-49). The median time to CR/CRh was 3 months (range 1-10). CR was achieved in 18/67 (27%; 95% CI, 17-39) patients with median duration of 20 months (range 0-44). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI, 38-63) patients. In a subset analysis (N=51) excluding patients who had prior OLU exposure, CR/CRh was achieved in 19/51 (37%; 95% CI, 24-52) patients, and CR was achieved in 16/51 (31%; 95% CI, 19-46). Overall response was achieved in 30/51 (59%; 95% CI, 44-72). Duration of CR/CRh was identical for the subset of 51 patients to the full group of 67 patients.
The median overall survival was 13 months (95% CI, 9-19) in 67 patients, 24 months in overall responders, 30.6 months in patients with CR/CRh, and not reached (range 11.5, 55.3+) in patients with CR. Twelve patients (18%) who achieved remission went on to receive HSCT.
Among the full group (N=67), transfusion independence of red blood cells (RBC) and platelets was achieved in 29% and 33% of patients, respectively, who were dependent at baseline. In patients who achieved CR/CRh (n=21), transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively, who were dependent at baseline.
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, of which 2 (3%) were grade 3. Grade 3 or 4 Increases in ALT were reported in 1 patient, AST in 1, ALP in 1, and transaminases in 1. Four patients (6%) discontinued treatment due to an adverse event.
Conclusion: In the first reported analysis of a combination therapy with an mIDH1 inhibitor and an HMA focused on the relapsed/refractory AML setting, olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R mIDH1 AML.