{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:06:22Z","timestamp":1760144782632,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Asan Foundation","award":["2016-003"],"award-info":[{"award-number":["2016-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background and Objectives: Essential thrombocythemia (ET) is a myeloproliferative neoplasm that overproduces platelets and is associated with life-threatening thrombosis. Medical cytoreduction either with hydroxyurea (HU) or anagrelide (AG) is widely used, but drug intolerance or resistance are major concerns. Low-dose combination of HU and AG as an alternative strategy has been explored in various studies. It showed comparable response with acceptable toxicity in second-line settings for patients who experienced side effects from prior monotherapy. In this study, we evaluated the efficacy and safety of upfront combination for ET patients. Materials and Methods: From January 2018 to June 2022, a total of 241 ET patients with intermediate to high risk were enrolled. We identified 21 patients with initial drug combinations and compared treatment outcomes and adverse events (AEs) between combination and monotherapy groups. Results: The median age was 62 years old (range, 26\u201387) and median platelet count was 912 \u00d7 109\/L (range, 520\u20131720). Overall treatment response did not exhibit significant differences between the groups, although there was a trend towards a lower response rate in patients treated with AG alone at 3 months post-treatment (AG + HU, 85.7% vs. AG alone, 75.4%, p = 0.068). AEs of any grade occurred in 52.3% of the combination group, 44.3% of the HU monotherapy group, and 43.4% of the AG single group, respectively. Of note was that the HU plus AG combination group suffered a lower incidence of grade 3\u20134 AEs compared to the other two groups, with statistical significance (p = 0.008 for HU monotherapy vs. combination therapy and p &lt; 0.01 for AG monotherapy vs. combination therapy). Conclusions: Our findings demonstrated that the upfront low-dose combination approach showed feasible clinical outcomes with significantly lower severe AEs compared to conventional monotherapy. These results may offer valuable insights to clinicians for future prospective investigations.<\/jats:p>","DOI":"10.3390\/jcm13102901","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:59:37Z","timestamp":1715677177000},"page":"2901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Initial Low-Dose Hydroxyurea and Anagrelide Combination in Essential Thrombocythemia: Comparable Response with Lower Toxicity"],"prefix":"10.3390","volume":"13","author":[{"given":"Young Hoon","family":"Park","sequence":"first","affiliation":[{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University Medical Center Mokdong Hospital, Seoul 07985, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeung-Chul","family":"Mun","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University Medical Center Mokdong Hospital, Seoul 07985, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-6856","authenticated-orcid":false,"given":"Sewon","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University Medical Center Mokdong Hospital, Seoul 07985, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0654-6664","authenticated-orcid":false,"given":"Yongchel","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung 25440, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.blre.2016.06.001","article-title":"The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances","volume":"30","author":"Barbui","year":"2016","journal-title":"Blood Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1002\/ajh.26008","article-title":"Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management","volume":"95","author":"Tefferi","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJM199504273321704","article-title":"Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis","volume":"332","author":"Cortelazzo","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa043800","article-title":"Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia","volume":"53","author":"Harrison","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1182\/blood-2012-07-443770","article-title":"Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: The ANAHYDRET Study, a randomized controlled trial","volume":"121","author":"Gisslinger","year":"2013","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/s41375-018-0077-1","article-title":"Philadelphia chromosome-negative classical myeloproliferative neoplasms: Revised management recommendations from European LeukemiaNet","volume":"32","author":"Barbui","year":"2018","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1365-2141.2010.08430.x","article-title":"Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance\/intolerance to hydroxycarbamide in essential thrombocythaemia","volume":"152","author":"Gomez","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3904\/kjim.2020.319","article-title":"The 2020 revision of the guidelines for the management of myeloproliferative neoplasms","volume":"36","author":"Kim","year":"2021","journal-title":"Korean J. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S300","DOI":"10.1016\/j.clml.2013.05.015","article-title":"Successful long-term treatment of Philadelphia chromosome-negative myeloproliferative neoplasms with combination of hydroxyurea and anagrelide","volume":"13","author":"Ahn","year":"2013","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1002\/cncr.20646","article-title":"Anagrelide for thrombocytosis in myeloproliferative disorders: A prospective study to assess efficacy and adverse event profile","volume":"101","author":"Steurer","year":"2004","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3324\/haematol.2012.083097","article-title":"Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid(R) efficacy and long-term safety study","volume":"99","author":"Gugliotta","year":"2014","journal-title":"Haematologica"},{"key":"ref_13","first-page":"1141","article-title":"Clinical Evaluation of the Efficacy and Safety of Anagrelide Used with or without Hydroxycarbamide in Japanese Patients with Essential Thrombocythemia\u2014A Retrospective Single-Center Study of 35 Cases","volume":"46","author":"Sekiguchi","year":"2019","journal-title":"Gan To Kagaku Ryoho Cancer Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1080\/10428190802353625","article-title":"The combined use of hydroxyurea and anagrelide allows satisfactory hematologic control in patients with chronic myeloproliferative disorders and thrombocytosis: A report on 13 patients with poor tolerance to hydroxyurea monotherapy","volume":"49","author":"Micheletti","year":"2008","journal-title":"Leuk. Lymphoma"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000189381","article-title":"Hydroxyurea and anagrelide combination therapy in patients with chronic myeloproliferative diseases resistant or intolerant to monotherapy","volume":"120","author":"Christoforidou","year":"2008","journal-title":"Acta Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5128","DOI":"10.1182\/blood-2012-07-444067","article-title":"Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis)","volume":"120","author":"Barbui","year":"2012","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/ejh.13265","article-title":"Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naive essential thrombocythemia patients in a real-world setting","volume":"103","author":"Ito","year":"2019","journal-title":"Eur. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mehy.2010.08.023","article-title":"Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signalling and clinical applications","volume":"76","author":"Kovacic","year":"2011","journal-title":"Med. Hypothesis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/sj.bjp.0706341","article-title":"Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures","volume":"146","author":"Wang","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mizzi, C.A., Dalabira, E., Kumuthini, J., Dzimiri, N., Balogh, I., Ba\u015fak, N., B\u00f6hm, R., Borg, J., Borgiani, P., and Bozina, N. (2016). A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162866"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kato, T., Ono, H., Fujii, M., Akahoshi, K., Ogura, T., Ogawa, K., Ban, D., Kudo, A., Tanaka, S., and Tanabe, M. (2021). Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252917"},{"key":"ref_22","first-page":"1905","article-title":"PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth","volume":"9","author":"An","year":"2019","journal-title":"Am. J. Cancer Res."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/10\/2901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:42:14Z","timestamp":1760107334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/10\/2901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,14]]},"references-count":22,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["jcm13102901"],"URL":"https:\/\/doi.org\/10.3390\/jcm13102901","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2024,5,14]]}}}