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

Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is US Food and Drug Administration approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia based on results from the pivotal cohort of a multiarm phase 1/2 trial that also enrolled patients with myelodysplastic syndrome (MDS). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naïve (TN) higher-risk mIDH1 MDS. Twenty-two patients (median age, 74 years; 59% male) with intermediate- to very high-risk MDS (monotherapy, n = 6 [4 R/R and 2 TN]; combination, n = 16 [11 R/R and 5 TN]) were analyzed. The most frequent adverse events were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%), including 1 (5%) with grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (complete remission [CR], 6/22 [27%]; marrow CR, 7/22 [32%]) in intent-to-treat (ITT; n = 22) and 68% (CR, 6/19 [32%]; marrow CR, 7/19 [37%]) in response-evaluable patients (n = 19). ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received half the recommended dose or less) and 69% (11/16) for combination therapy. Median time to response was 2 months (range, 1-13), median duration of response was 14.6 months (95% confidence interval [CI], 5.8-32.8), and median overall survival was 27.2 months (95% CI, 6.9-37). Sixty-two percent and 67% of patients who were transfusion dependent at baseline achieved 56-day red blood cell and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. This trial was registered at www.ClinicalTrials.gov as #NCT02719574.