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Higher-risk MDS (HR-MDS), defined by the Revised International Prognostic Scoring System score of \u2a7e3.5, is characterized by increased myeloblasts, severe cytopenia, and a median survival of &lt;2\u2009years. The pathogenesis involves complex genetic mutations, cytogenetic abnormalities, and a dysregulated bone marrow microenvironment. Current standard therapies, such as hypomethylating agents and allogeneic stem cell transplantation, are often inadequate, especially in older patients with comorbidities and limited clinical trial eligibility. This review highlights emerging targeted therapies for older HR-MDS patients, focusing on small-molecule agents for their critical advantages like patient-friendly oral delivery, lower production barriers, improved access to intracellular targets, and flexible dosing strategies. Venetoclax, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has shown promise in clinical trials but requires further validation. Isocitrate dehydrogenase 1 (IDH1) inhibitors, including ivosidenib and olutasidenib, have demonstrated efficacy and tolerability, while ongoing investigations explore other novel agents like IDH2 inhibitors and FMS-like tyrosine kinase 3 (FLT3) inhibitors. By summarizing the latest advancements, this review emphasizes the importance of developing safe, effective, and personalized therapies to improve outcomes and quality of life for older patients with HR-MDS, with a focus on age-specific clinical trials.<\/jats:p>","DOI":"10.1177\/20406207251371298","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:42:26Z","timestamp":1756964546000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel small-molecule therapies for myelodysplastic syndromes with IPSS-R \u2a7e3.5 in patients aged 60 or older: current landscape and challenges"],"prefix":"10.1177","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1869-8420","authenticated-orcid":false,"given":"Kehao","family":"Hou","sequence":"first","affiliation":[{"name":"Qingdao University Qingdao Medical College, Qingdao, Shandong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5119-2599","authenticated-orcid":false,"given":"Xue","family":"Dong","sequence":"additional","affiliation":[{"name":"Qingdao University Qingdao Medical College, Qingdao, Shandong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0962-9715","authenticated-orcid":false,"given":"Wenyan","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14194941"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.283175"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000790"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-024-00733-y"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2020.100791"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2024.03.006"},{"issue":"7","key":"e_1_3_4_8_2","first-page":"2157","article-title":"Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia","volume":"109","author":"Jain AG","year":"2024","unstructured":"Jain AG, Ball S, Aguirre L, et al. 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