PMID- 32647323
OWN - NLM
STAT- MEDLINE
DCOM- 20210113
LR  - 20220613
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 35
IP  - 1
DP  - 2021 Jan
TI  - Fedratinib, a newly approved treatment for patients with myeloproliferative 
      neoplasm-associated myelofibrosis.
PG  - 1-17
LID - 10.1038/s41375-020-0954-2 [doi]
AB  - Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized 
      by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary 
      hematopoiesis, splenomegaly, and shortened survival. 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 JAK2V617F-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 h). Fedratinib showed 
      robust clinical activity in JAK-inhibitor-naive 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 1-2 months of treatment. 
      The most common adverse events (AEs) with fedratinib are grades 1-2 
      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's 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.
FAU - Talpaz, Moshe
AU  - Talpaz M
AUID- ORCID: 0000-0003-3361-3981
AD  - University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. 
      mtalpaz@umich.edu.
FAU - Kiladjian, Jean-Jacques
AU  - Kiladjian JJ
AUID- ORCID: 0000-0002-8121-438X
AD  - Hopital Saint-Louis, Universite de Paris, Inserm, Paris, France.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20200709
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Janus Kinase Inhibitors)
RN  - 0 (Pyrrolidines)
RN  - 0 (Sulfonamides)
RN  - 6L1XP550I6 (fedratinib)
RN  - EC 2.7.10.2 (Janus Kinases)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Clinical Trials as Topic
MH  - Cytokines/metabolism
MH  - Disease Susceptibility
MH  - Drug Monitoring
MH  - Humans
MH  - Janus Kinase Inhibitors/chemistry/pharmacology/*therapeutic use
MH  - Janus Kinases/antagonists & inhibitors/chemistry/genetics/metabolism
MH  - Molecular Targeted Therapy
MH  - Myeloproliferative Disorders/*complications/diagnosis
MH  - Primary Myelofibrosis/diagnosis/*drug therapy/*etiology/metabolism
MH  - Pyrrolidines/chemistry/pharmacology/*therapeutic use
MH  - Sulfonamides/chemistry/pharmacology/*therapeutic use
MH  - Treatment Outcome
PMC - PMC7787977
COIS- MT consulted for BMS and Celgene; received research funding from NS Pharma, 
      Incyte, Stemline, Janssen, Promedior, Gilead, CTI Biopharma, Novartis, Samus 
      Therapeutics, Asana, and Constellation; and received funding for travel and 
      accommodations expenses from BMS and Celgene. J-JK consulted for Novartis, Roche, 
      Celgene, and AOP Orphan; received research funding from Novartis; and received 
      funding for travel and accommodations expenses from Celgene.
EDAT- 2020/07/11 06:00
MHDA- 2021/01/14 06:00
PMCR- 2020/07/09
CRDT- 2020/07/11 06:00
PHST- 2020/02/14 00:00 [received]
PHST- 2020/06/25 00:00 [accepted]
PHST- 2020/06/15 00:00 [revised]
PHST- 2020/07/11 06:00 [pubmed]
PHST- 2021/01/14 06:00 [medline]
PHST- 2020/07/11 06:00 [entrez]
PHST- 2020/07/09 00:00 [pmc-release]
AID - 10.1038/s41375-020-0954-2 [pii]
AID - 954 [pii]
AID - 10.1038/s41375-020-0954-2 [doi]
PST - ppublish
SO  - Leukemia. 2021 Jan;35(1):1-17. doi: 10.1038/s41375-020-0954-2. Epub 2020 Jul 9.