Oral eltanexor treatment of patients with higher-risk myelodysplastic syndrome refractory to hypomethylating agents

Abstract

Patients with higher-risk myelodysplastic syndromes (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and an expected overall survival (OS) of 3-5 months. Eltanexor is an investigational oral selective inhibitor of nuclear export with low central nervous system penetrance and an acceptable tolerability profile. Preclinical studies suggest that myeloid malignancies are sensitive to nuclear export inhibition. Eltanexor exhibited efficacy in hematologic models, supporting exploration in a clinical trial. This phase 1/2 study (NCT02649790) assessed single-agent activity of eltanexor in patients with higher-risk MDS and 5-19% myeloblasts. Two starting doses of eltanexor were evaluated: 20 mg (n = 15), 10 mg (n = 5), both administered on days 1-5 each week of a 28-day cycle. Twenty patients with primary HMA-refractory MDS, with a median age of 77 years (range 62-89), and a median of two prior treatment regimens (range 1-4) were enrolled. Of these, 15 were evaluated for efficacy and 20 for safety. The overall response rate (ORR) was 53.3%, with seven patients (46.7%) achieving marrow complete remission (mCR) and one additional patient achieving hematologic improvement (HI). In the 10 mg group, three patients (60%) reached mCR and two (40%) stable disease (SD), while for 20 mg, four patients (40%) had mCR and two (20%) SD. A total of three patients (20%) had HI and became transfusion independent ≥ 8 weeks. Median OS for the efficacy-evaluable patients (n = 15) was 9.86 months (7.98, NE). Overall, the most frequently reported treatment-related adverse events were nausea (45%), diarrhea (35%), decreased appetite (35%), fatigue and neutropenia (both 30%). Single-agent oral eltanexor was active, safe, and well tolerated in patients with higher-risk, primary HMA-refractory MDS.

Conflict of interest statement

SL reports consultancy for Abbvie, AstraZeneca, BMS, Innate, Pin Therapeutics, and employment at Janssen Research and Development. SM reports research funding from Incyte, Karyopharm, and Taiho. JK, KC, AD, FY, and EB are all current employees of Karyopharm Therapeutics Inc. MK and SS are stockholders of Karyopharm Therapeutics Inc. JS, MK, and SS are former employees of Karyopharm Therapeutics Inc. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Overall Survival. The median OS for all patients was 9.86 months. OS was higher in mCR patients (n = 7) than patients who did not reach mCR (n = 8): median 11.86 vs 8.67 months (HR = 0.28, p = 0.11), and longer than OS for patients with PD (n = 3, mOS = 3.15 months, HR = 0.23, p = 0.08). mCR = marrow complete remission; OS = overall survival; HR = hazard ratio; PD = progressive disease