Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome Open Access

• Olutasidenib alone or with azacitidine elicited high response rates and durable remissions in intermediate- to very high-risk mIDH1 MDS

• The safety profile of olutasidenib+azacitidine was comparable to monotherapy with either agent; no new safety signal reported in combination

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 based on results from the pivotal AML cohort of a multi-arm phase 1/2 trial that also enrolled patients with MDS (NCT02719574). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naïve (TN) higher-risk MDS harboring mIDH1. Endpoints included safety, overall response rate (ORR), complete remission (CR) rate, time-to-response (TTR), duration of response (DOR), overall survival (OS), and transfusion-independence. Twenty-two patients (median age 74 years, 59% male) with IPSS-R intermediate- to very high-risk MDS (n=6 monotherapy [4 R/R, 2 TN]; n=16 combination [11 R/R, 5 TN]) were analyzed. The most frequent AEs were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%); 1(5%) grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (CR: 27%, 6/22; marrow CR: 32%, 7/22) in intent-to-treat (n=22, ITT) and 68% (CR: 32%, 6/19; marrow CR: 37%, 7/19) in response-evaluable (n=19) patients. ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received £half the recommended dose) and 69% (11/16) for combination therapy. Median TTR was 2 months (range 1-13), median DOR 14.6 months (95% CI, 5.8-32.8), and median OS 27.2 months (95% CI, 6.9-37). 62% and 67% of patients who were transfusion-dependent at baseline achieved 56-day RBC and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574