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Constitutive activation of the janus kinase\/signal transducer and activator of transcription (JAK\/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of <jats:italic>JAK2<\/jats:italic>V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK\/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41\u2009h). Fedratinib showed robust clinical activity in JAK-inhibitor-na\u00efve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1\u20132 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1\u20132 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke\u2019s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.<\/jats:p>","DOI":"10.1038\/s41375-020-0954-2","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T12:05:17Z","timestamp":1594296317000},"page":"1-17","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":184,"title":["Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis"],"prefix":"10.1038","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-3981","authenticated-orcid":false,"given":"Moshe","family":"Talpaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8121-438X","authenticated-orcid":false,"given":"Jean-Jacques","family":"Kiladjian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"954_CR1","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/ajh.24592","volume":"91","author":"A Tefferi","year":"2016","unstructured":"Tefferi A. 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