Abstract
Background: Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by ineffective hematopoiesis, persistent peripheral cytopenias, and a risk of progression to acute myeloid leukemia (AML). Severe thrombocytopenia is associated with a high risk of bleeding and an unfavorable prognosis in lower-risk MDS (LR-MDS). Currently, treatment remains largely limited to platelet transfusions, as effective pharmacologic options are scarce and often associated with significant adverse effects, highlighting an unmet need in clinical practice. Hetrombopag, a novel non-peptide thrombopoietin receptor agonist (TPO-RA), has demonstrated efficacy and mild adverse effects in immune thrombocytopenia and aplastic anemia. This study assessed the efficacy and safety of hetrombopag in LR-MDS patients with thrombocytopenia. Methods: In this prospective, single-arm, multicenter study, eligible patients had a primary MDS according to World Health Organization (WHO) 2022 criteria, with very low, low, or intermediate-risk based on the Revised International Prognostic Scoring System (IPSS-R) classification, and exhibiting < 5% bone marrow blasts. Patients were required to have baseline platelet count ≤30×10⁹/L and received oral hetrombopag 15 mg/day for 24 weeks. Dose adjustments were permitted based on platelet counts and toxicities. Supportive therapies (blood transfusions, granulocyte colony-stimulating factor, and/or erythropoiesis stimulating agents) were allowed, but other platelet- increasing agents were prohibited. The primary endpoint was the platelet response rate within 24 weeks, defined per the modified 2006 International Working Group (IWG) response criteria for MDS. The study is registered at ChiCTR.org.cn (ChiCTR2300068232).Results: Between February 20, 2023 and April 3, 2025,a total of 43 patients were enrolled (median age 57.0 years; 51.2% female). Most patients had IPSS-R intermediate-risk (58.1%, n=25) and MDS with low blasts (MDS-LB, 88.4%, n=38). The median platelet was 19×10⁹/L (interquartile range [IQR], 15-22) at baseline. As of July 2025, 18 of 43 patients (41.9%, 95% confidence interval [CI]: 27.4-57.8) achieved platelet responses, including three (7.0%) who achieved complete responses. Twelve of 43 patients (27.9%; 95% CI: 15.7-43.4) achieved platelet counts ≥50×10⁹/L. The median time to response was 7.0 weeks (IQR. 4.1-15.6). Univariate logistic regression revealed no significant associations between platelet response and baseline characteristics including age, gender, IPSS-R risk category, MDS subtype, Eastern Cooperative Oncology Group (ECOG) performance status, or the presence of gene mutations (e.g., BCOR, DNMT3A, U2AF1 or ASXL1). Treatment-emergent adverse events (TEAEs) occurred in 13 patients (30.2%), with infection being the most frequent (5 patients, 11.6%). Grade 3-4 infection occurred in four patients (9.3%). No treatment-related deaths occurred.Conclusion: Hetrombopag is effective in increasing platelet counts and demonstrates an acceptable toxicity profile in LR-MDS patients with thrombocytopenia, suggesting that hetrombopag may be a promising new therapeutic option for this population. Nevertheless, further larger, prospective and controlled studies are warranted to better define the role of hetrombopag in the treatment of LR-MDS.
