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Currently, the management of MF patients is tailored according to risk scores, with higher\u2010risk (intermediate\u20102 and high\u2010risk) patients being assessed for allogeneic stem cell transplantation, which remains the only potentially curative treatment option. On the other hand, lower risk (low\u2010 and intermediate\u20101 risk) patients who are symptomatic may be treated with JAK inhibitors or other drugs. However, none of these drug treatments have induced relevant rates of durable complete remissions, and, therefore, novel treatments are needed to improve the long\u2010term outcomes of MF patients. This review summarizes current preclinical and clinical approaches to MF therapy, including novel drug combinations involving JAK inhibitors and innovative monotherapies. These drugs target transcription, nuclear export, survival pathways, or various intracellular pathways, ranging from JAK\u2010STAT signaling to PI3\u2010Kinase, TP53, PIM1, or S100A8\/A9\/toll\u2010like receptor pathways. Also, extracellular targeting using interferon, calreticulin mutant\u2010specific antibodies, and other immunotherapeutic approaches are discussed, as well as various antifibrotic strategies. In addition, preclinical approaches that target individual mutated clones, for example, by mutation\u2010specific JAK2V617F inhibitors or DNA repair pathway inhibitors, are presented. Finally, current efforts of generating novel endpoints for clinical trials aim more at disease modification and overall survival than at improvements of splenomegaly or symptoms. Together, the new generations of clinical trials promise to offer substantial improvements in the management of MF patients and long\u2010term disease control.<\/jats:p>","DOI":"10.1002\/hem3.70056","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T12:23:52Z","timestamp":1734006232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel approaches in myelofibrosis"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1011-8171","authenticated-orcid":false,"given":"Steffen","family":"Koschmieder","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty RWTH Aachen University Aachen Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD) Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"issue":"2","key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1182\/blood-2011-01-328955","article-title":"The Myeloproliferative Neoplasm Symptom Assessment Form (MPN\u2010SAF): international prospective validation and reliability trial in 402 patients","volume":"118","author":"Scherber R","year":"2011","journal-title":"Blood"},{"issue":"12","key":"e_1_2_8_3_1","doi-asserted-by":"crossref","DOI":"10.3390\/cells10123551","article-title":"Progression of myeloproliferative neoplasms (MPN): diagnostic and therapeutic perspectives","volume":"10","author":"Baumeister J","year":"2021","journal-title":"Cells"},{"key":"e_1_2_8_4_1","unstructured":"GriesshammerM BaerlocherGM D\u00f6hnerK et al. Onkopedia guideline on \u201cprimary myelofibrosis\u201d;2023. 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