Olutasidenib Alone or in Combination with Azacitidine in Patients with mIDH1 Myelodysplastic Syndromes/Neoplasms: Final 5-Year Data
Authors: Cortes Jorge E. , Watts Justin M. , Wang Eunice S. , Yang Jay , Dinner Shira N. , Baer Maria R. , Roboz Gail J. , Donnellan William B. 
Published: December 2024

Introduction. Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is FDA approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML) based on results from the pivotal cohort (n=153) of a registrational phase 1/2 trial (NCT02719571). The study also enrolled adults with mIDH1 myelodysplastic syndromes/neoplasms (MDS); here we report the five-year results of olutasidenib in patients with mIDH1 MDS.
Methods. Patients with R/R or treatment-naïve (TN) mIDH1 MDS (intermediate, high or very-high risk by IPSS-R) were included. Olutasidenib was given at 150 mg BID or 100-150 mg QD as monotherapy, or as a combination of olutasidenib 150 mg BID plus azacitidine (75 mg/m2 daily x 7 days/28-day cycles). The primary efficacy endpoints were safety (phase 1) and complete remission (CR; based on IWG in MDS 2006) rates. Secondary endpoints included overall response (CR/partial remission [PR]/marrow CR), time to response (TTR), duration of response (DOR), and safety (phase 2).
Results. At data cut-off (16 June 2023), 22 patients with MDS were included from the phase 1/2 studies; 6 received monotherapy (4 R/R, 2 TN) and 16 received combination therapy (11 R/R, 5 TN). Median age was 74 (range 59-87) years; 59% were male, and 86% had baseline ECOG of 0 or 1. MDS was high-risk in 68% and very high-risk in 18%. Patients had had a median of 1 (range 1-4) prior regimen for MDS; 64% had a prior hypomethylating agent and 1 had a prior stem cell transplant.
For the pooled phase 1/2 data, overall response rate (ORR) was 59% (CR: 27%; marrow CR: 32%). ORR with monotherapy was 33% (CR: 17%; marrow CR: 17%), including 2/3 (66%) with the approved dose of 150 mg BID and 0/3 with the lower doses of 100-150 mg QD, and ORR with combination therapy was 11/16 (69%). Median TTR was 2.0 months. Median DOR was 14.6 months (range 0.0 to 52.0), and median duration of CR was 20.5 months (range 0.0 to 52.0). Overall survival was 27.2 months (range 0.0 to 67.0). Three patients proceeded to stem cell transplant.
Of 7 patients (32%) experiencing marrow CR (mCR), 4 (57%) experienced hematological improvement in ≥1 lineage (erythrocyte, platelet and/or neutrophil); 3 (43%) had an improvement in erythrocyte counts, 3 (43%) in platelet counts, and 4 (57%) in neutrophil counts (mIWG 2006 response criteria).
In a subanalysis of the 19 efficacy evaluable patients,11/14 (79%) responded to combination therapy and 2/5 (40%) responded to monotherapy, which included 2/2 (100%) using the approved dose of 150 mg BID olutasidenib.
All patients reported adverse events (AEs), and the most common were fatigue, nausea, constipation, arthralgia, decreased platelet counts, and vomiting. Grade 3 and Grade 4 AEs occurred in 19 (86%) and 9 (41%) patients, respectively; cytopenias were most frequently reported. Differentiation syndrome occurred in 3 patients (Grade 3 in 1 patient). Grade 3 or 4 elevation in alanine transaminase occurred in 3 (14%) patients.
Conclusions. Patients with intermediate- to very high-risk mIDH1 MDS treated with olutasidenib monotherapy or in combination with azacitidine demonstrated encouraging response rates with durable remissions and an acceptable and manageable safety profile.