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Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed\/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved \u22651-year RBC-TI. Additionally, higher rates of \u22651-year RBC-TI were observed in patients with maximum variant allele frequency reduction of \u226550% in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    (58% vs. 7%),\n                    <jats:italic>TET2<\/jats:italic>\n                    (90% vs. 9%),\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    (100% vs. 13%), or\n                    <jats:italic>ASXL1<\/jats:italic>\n                    (50% vs. 0%) and patients with \u226550% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with \u22651-year RBC-TI had \u226550% reduction in telomerase activity\/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02831-z","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:23:56Z","timestamp":1768213436000},"page":"397-409","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modulation of the clonal burden in patients with lower-risk myelodysplastic neoplasms treated with imetelstat"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-2172","authenticated-orcid":false,"given":"Valeria","family":"Santini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amer M.","family":"Zeidan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8285-906X","authenticated-orcid":false,"given":"Koen","family":"Van Eygen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Fenaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Germing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9573-2690","authenticated-orcid":false,"given":"Yazan F.","family":"Madanat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azra","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Savona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2009-6524","authenticated-orcid":false,"given":"Mikkael A.","family":"Sekeres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Th\u00e9pot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0764-6105","authenticated-orcid":false,"given":"Marco G.","family":"Raddi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8133-5491","authenticated-orcid":false,"given":"Thomas","family":"Boyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tymara","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souria","family":"Dougherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyamala","family":"Navada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faye","family":"Feller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-5269","authenticated-orcid":false,"given":"Rami S.","family":"Komrokji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1863-3239","authenticated-orcid":false,"given":"Uwe","family":"Platzbecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"2831_CR1","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1056\/NEJMra1904794","volume":"383","author":"M Cazzola","year":"2020","unstructured":"Cazzola M. 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AMZ received research funding (institutional) from Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, AbbVie, Astex Pharmaceuticals, Pfizer, Kura Oncology, MedImmune\/AstraZeneca, Boehringer Ingelheim, Incyte Corporation, Takeda, Novartis, Shattuck Labs, Geron Corporation, Foran Pharmaceuticals, and Aprea Therapeutics; participated in advisory boards, had a consultancy with, or received honoraria from AbbVie, Pfizer, Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, Jazz Pharmaceuticals, Incyte Corporation, Agios Pharmaceuticals, Servier, Boehringer Ingelheim, Novartis, Astellas Pharma, Daiichi Sankyo, Geron Corporation, Taiho Oncology, Seattle Genetics, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax Pharmaceuticals, Gilead, Kura Oncology, Chiesi, ALX Oncology, BioCryst, Notable Labs, Orum Therapeutics, Mendus, Zentalis Pharmaceuticals, Regeneron, Syros Pharmaceuticals, Schr\u00f6dinger, and Tyme Technologies; and served on clinical trial committees for Novartis, AbbVie, Gilead, Syros Pharmaceuticals, BioCryst, ALX Oncology, Kura Oncology, Geron Corporation, and Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company. KVE has nothing to disclose. PF received consultancy fees, research funding, and honoraria from Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, and honoraria and research funding from Celgene. UG has nothing to disclose. YFM received honoraria or consulting fees from Blueprint Medicines, Geron Corporation, and OncLive; participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, MorphoSys, Taiho Oncology, and Novartis; and received travel reimbursement from Blueprint Medicines and MorphoSys. AR received patents and royalties, and was a member on the Board of Directors or advisory committee of TFC Therapeutics. MRS received research funding from ALX Oncology, Astex Pharmaceuticals, Incyte Corporation, Takeda, and TG Therapeutics; consults or serves on advisory or data safety monitoring boards for AbbVie, Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, Forma Therapeutics, Geron Corporation, Karyopharm Therapeutics, Novartis, Rigel Pharmaceuticals, Ryvu Therapeutics, Sierra Oncology, Taiho Oncology, Takeda, TG Therapeutics, and Treadwell Therapeutics; and has equity in Empath Biosciences, Karyopharm Therapeutics, and Ryvu Therapeutics. MAS received advisory board fees from Geron Corporation, Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, Novartis, and Kurome Therapeutics. ST received advisory board fees or honoraria from Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, AbbVie, Gilead, Astellas Pharma, and Takeda. MGR and TB declare no competing interests. LS, YW, TB, QX, FH, SD, SN, and FF are employees of Geron Corporation. RSK participated on a speakers\u2019 bureau with Jazz Pharmaceuticals, Servier, AbbVie, CTI BioPharma, and PharmaEssentia; received advisory board fees or honoraria from Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, Novartis, AbbVie, Jazz Pharmaceuticals, Servier, PharmaEssentia, Taiho Oncology, Takeda, Geron Corporation, Gilead\/Forty Seven, and CTI BioPharma; received travel accommodations and expenses from Jazz Pharmaceuticals, Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, and PharmaEssentia; has stock and other ownership interests in AbbVie; and received research funding from Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company. UP received honoraria, consultancy fees, and research funding from Geron Corporation, Bristol Myers Squibb\/Celgene, a Bristol Myers Squibb Company, AbbVie, Jazz Pharmaceuticals, Janssen, Syros Pharmaceuticals, Servier, Silence Therapeutics, and Takeda.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}