Ivosidenib monotherapy in IDH1 mutated myelodysplastic neoplasm/syndrome.

Ivosidenib (IVO) is an oral inhibitor of mutant IDH1 (IDH1m) approved for treatment of IDH1m acute myeloid leukemia (AML) in association with Azacitidine (AZA). We investigated safety and efficacy of IVO monotherapy in patients with IDH1m myelodysplastic neoplasm/syndrome (MDS). This multicenter phase 2 trial enrolled three cohorts: high-risk (HR-) relapse or refractory (R/R) patients after AZA (cohort A), treatment-naïve HR-patients (cohort B) and low-risk patients refractory to erythropoiesis-stimulating agents (cohort C). All patients received 28-day cycles of IVO at 500 mg once daily. Between 2019 and 2023, 48 patients were included (median age 76.5 years). The ORR after 3 cycles was 63.6% (95%CI, 40.7-82.8) in cohort A, and 78.3% (95%CI, 56.3-92.5) in cohort B; the 12-month OS rate in cohorts A and B was 18.2% (95%CI, 7.5-44.1) and 91.3% (95%CI, 80.5-100), respectively. In cohort C, no significant toxicities were reported. Higher baseline IDH1 mutant clone size predicted response, whereas TP53 or IDH2 co-mutations were associated with resistance. Molecular clearance was not required for clinical benefit. IVO monotherapy was well tolerated and demonstrated sustained clinical activity across all IDH1m cohorts representing a potential therapeutic breakthrough in this frail population, particularly as a first-line therapeutic option in treatment naïve IDH1m HR-MDS patients (IDIOME, NCT03503409).