<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

Abstract

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.

Kinase inhibition in autoimmunity and inflammation

“…Ruxolitinib inhibits JAK2 and, to a lesser extent, JAK1 and JAK3, and is approved for myelofibrosis and polycythemia vera 45 . Fedratinib targets JAK2 and was recently approved for myelofibrosis, showing significant improvements in symptoms and a reduction in spleen size 46 .…”

JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells

“…Fedratinib is an oral JAK2 inhibitor [ 28 ] that has been recently approved by the Food and Drug Administration to treat adults with myelofibrosis based on the significant improvements reported in phase II and III clinical trials, which renders this drug the second to be approved for myelofibrosis, after ruxolitinib, a JAK1/2 inhibitor. Fedratinib exhibited clinical efficiency in ruxolitinib-resistant patients [ 29 , 30 ]. Myelofibrosis is a myeloproliferative neoplasm characterised by bone-marrow fibrosis, cytopenia, extramedullary hematopoiesis, and splenomegaly [ 29 ].…”

Cardiotoxicity of Novel Targeted Hematological Therapies

“…All known BCR/ABL fusion protein variants are composed by an ABL tyrosine kinase domain constitutionally active downstream of various signaling pathways, such as PI3K and STAT, involved in gene expression, mRNA processing and maturation, and protein stability [ 73 , 74 ]. In HSC compartment, deregulation of these pathways translates in increased cell survival and proliferation, and impaired differentiation with suppression of granulocyte maturation [ 74 ].…”

“…In HSC compartment, deregulation of these pathways translates in increased cell survival and proliferation, and impaired differentiation with suppression of granulocyte maturation [ 74 ]. Imatinib, the first-in-class oral TKI approved for treatment of CML in 2001, has pharmacological activity against ABL, BCR/ABL, platelet-derived growth factor receptor A (PDGFRA), and c-KIT on neoplastic cells, and also against ABL on normal cells [ 73 ]. Imatinib binds amino acid residues in the ATP binding site and stabilizes the inactive forms preventing autophosphorylation and thus switching off signaling transduction [ 74 ].…”