Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis

Abstract

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-naïve 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.

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…Treatment with ruxolitinib showed some reduction in JAK2 V617F mutant allele burden in PV patients [ 74 , 75 ], although its effect on reduction of mutant allele burden in MF is mild [ 76 ]. Additionally, several second generation JAK inhibitors were developed to improve efficacy and reduce side effects of ruxolitinib [ 77 , 78 , 79 , 80 , 81 ]. However, none of them show significance in eradicating LSCs [ 77 , 79 , 80 , 82 , 83 ].…”

“…Additionally, several second generation JAK inhibitors were developed to improve efficacy and reduce side effects of ruxolitinib [ 77 , 78 , 79 , 80 , 81 ]. However, none of them show significance in eradicating LSCs [ 77 , 79 , 80 , 82 , 83 ]. Some studies have shown that fedratinib, a newly FDA approved JAK2/FLT3 inhibitor in 2019, reduced JAK2 V617F variant allele frequency (VAF) [ 79 , 84 ].…”

“…However, none of them show significance in eradicating LSCs [ 77 , 79 , 80 , 82 , 83 ]. Some studies have shown that fedratinib, a newly FDA approved JAK2/FLT3 inhibitor in 2019, reduced JAK2 V617F variant allele frequency (VAF) [ 79 , 84 ]. Yet, the results were not consistent with other trials [ 79 , 83 , 85 ].…”

“…Some studies have shown that fedratinib, a newly FDA approved JAK2/FLT3 inhibitor in 2019, reduced JAK2 V617F variant allele frequency (VAF) [ 79 , 84 ]. Yet, the results were not consistent with other trials [ 79 , 83 , 85 ]. Therefore, combinations of various novel therapies with ruxolitinib emerge in the hope of eliminating MPN LSCs [ 86 ].…”

JAK-Inhibitoren für die Behandlung hämatoonkologischer Erkrankungen

“…In diesen Studien wurde Fedratinib in JAK-Inhibitor-naiven beziehungsweise in mit Ruxolitinib vorbehandelten Patienten getestet und zeigte in Bezug auf Symptomkontrolle und Reduktion der Milzgröße Ergebnisse, die mit denen von Ruxolitinib aus den klinischen Studien COMFORT-I und COMFORT-II vergleichbar waren [21,52]. Häufigste Nebenwirkungen, die Dosisreduktionen erforderten, bestanden wiederum in Anämie und Thrombozytopenie, die als sogenannte on-target-Effekte für die JAK2-Hemmung typisch sind [41] sowie in gastrointestinalen Symptomen, die am ehesten als off-target-Effekte aus der FLT3-Hemmung resultieren [53]. Wegen des Verdachts auf ein erhöhtes Auftreten von neurologischen Komplikationen, im Speziellen einer Wernicke-Enzephalopathie, wurden die klinischen Studien zu Fedratinib zwischenzeitlich ausgesetzt.…”