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Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat

Oppliger Leibundgut, Elisabeth, Haubitz, Monika, Burington, Bart, Ottmann, Oliver G., Spitzer, Gary, Odenike, Olatoyosi, McDevitt, Michael A., Röth, Alexander, Snyder, David S. and Baerlocher, Gabriela M. 2021. Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat. Haematologica 106 (9) , pp. 2397-2404. 10.3324/haematol.2020.252817

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In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. ( number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.)

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Publisher: Ferrata Storti Foundation
ISSN: 1592-8721
Date of First Compliant Deposit: 26 January 2022
Date of Acceptance: 21 July 2020
Last Modified: 05 Apr 2022 12:30

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