Background: Patients (pts) with myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and a dismal prognosis with a median overall survival (mOS) of 4-6 months. Eltanexor (ELTA) is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound that showed anti-tumor activity and lower brain penetration compared to selinexor (SEL) in nonclinical models. It was hypothesized that ELTA could be dosed more frequently than SEL with a lower incidence of centrally mediated nausea. Early results from a phase 1/2 study of ELTA in pts with HMA refractory MDS showed anti-tumor activity with marrow complete response (mCR) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee et al. ASH 2019). In this abstract, we provide a subgroup analysis of the efficacy evaluable population with an update on mOS in the same population. Methods: This phase 1/2 study (NCT02649790) evaluated single-agent ELTA in pts with higher-risk MDS, ie, high-risk or intermediate-2 MDS by International Prognostic Scoring System (IPSS) and 5%-19% myeloblasts. Out of 20 pts enrolled, 15 pts were evaluable for efficacy and constitute the population studied in this analysis. Two doses of ELTA were evaluated: 10 mg (n=5) or 20 mg (n=15) every day for 5 days per week of a 28-day cycle. Results: As of 1 Feb 2021, the 15 pts evaluable for efficacy (median age 76 years; range 62-89) had a median of 2 prior treatment regimens (range 1-4); 93% had high/int-2 risk per IPSS. Of the 20 enrolled patients, 7 (35%) had mCR, and 5 (25%) had SD for a total disease control (mCR+SD) rate of 60%. Of the 15 pts evaluable for efficacy, 7 (47%) had mCR and 5 (33%) had SD. In the 10-mg cohort (n=5), all pts derived clinical benefit with 3 pts (60%) reaching mCR and 2 pts (40%) SD. In the 20-mg cohort (n=10), 4 pts (40%) had mCR and 3 (30%) had SD. Four pts had hematologic improvement (HI) and became transfusion independent for at least 8 weeks including 2 pts with tri-lineage HI. OS for pts who reached mCR (n=7) was significantly longer than for pts who did not reach mCR (n=8): median 11.86 vs 8.67 months (mo) (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for pts with PD (n=3, mOS=3.15 mo, HR=0.23, p=0.04). Pts with disease control (n=12) had numerically longer mOS than pts with PD (9.86 vs 3.15 mo, HR=0.38, p=0.09). Pts with HI had a mOS of 10.58 months. Conclusions: Single-agent oral ELTA was active in pts with high-risk, HMA refractory MDS. Pts with mCR had significantly longer mOS than pts without mCR or with PD. Further evaluation of ELTA in MDS as a single agent and in combination with other agents is ongoing. Clinical trial information: NCT02649790