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Additional disease features include bone marrow reticulin\/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Diagnosis<\/jats:title><jats:p>Bone marrow morphology is the primary basis for diagnosis. Presence of <jats:italic>JAK2<\/jats:italic>, <jats:italic>CALR<\/jats:italic>, or <jats:italic>MPL<\/jats:italic> mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes \u201cprefibrotic\u201d from \u201covertly fibrotic\u201d PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF\u2010like phenotype (post\u2010ET\/PV MF) during their clinical course.<\/jats:p><\/jats:sec><jats:sec><jats:title>Adverse Mutations<\/jats:title><jats:p><jats:italic>SRSF2<\/jats:italic>, <jats:italic>ASXL1<\/jats:italic>, and <jats:italic>U2AF1<\/jats:italic>\u2010Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. <jats:italic>RAS\/CBL<\/jats:italic> mutations predicted resistance to ruxolitinib therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Adverse Karyotype<\/jats:title><jats:p>Very high risk abnormalities include \u22127, inv (3), i(17q), +21, +19, 12p\u2010, and 11q\u2010.<\/jats:p><\/jats:sec><jats:sec><jats:title>Risk Stratification<\/jats:title><jats:p>Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically\u2010inspired prognostic scoring system) and MIPSS70+ <jats:italic>version 2.0<\/jats:italic> (MIPSS<jats:italic>v2<\/jats:italic>; mutation\u2010 and karyotype\u2010enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSS<jats:italic>v2<\/jats:italic> includes, in addition, clinical risk factors. GIPSS features four and MIPSS<jats:italic>v2<\/jats:italic> five risk categories.<\/jats:p><\/jats:sec><jats:sec><jats:title>Risk\u2010adapted Therapy<\/jats:title><jats:p>Observation alone is advised for MIPSS<jats:italic>v2<\/jats:italic> \u201clow\u201d and \u201cvery low\u201d risk disease (estimated 10\u2010year survival 56%\u201092%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for \u201cvery high\u201d and \u201chigh\u201d risk disease (estimated 10\u2010year survival 0%\u201013%); treatment\u2010requiring patients with intermediate\u2010risk disease (estimated 10\u2010year survival 30%) are best served by participating in clinical trials. In non\u2010transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA\u2010approved for use in ruxolitinib failures. Splenectomy is considered for drug\u2010refractory splenomegaly and involved field radiotherapy for non\u2010hepatosplenic EMH and extremity bone pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>New Directions<\/jats:title><jats:p>A number of new agents, alone or in combination with ruxolitinib, are currently under investigation for MF treatment (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>); preliminary results from some of these clinical trials were presented at the 2020 ASH annual meeting and highlighted in the current document.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajh.26050","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T18:14:57Z","timestamp":1605550497000},"page":"145-162","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":294,"title":["Primary myelofibrosis: 2021 update on diagnosis, 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