Cancer Management and Research (Dec 2019)
Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis
Abstract
Jan Philipp Bewersdorf,1 Sara Mohamed Jaszczur,2 Salma Afifi,2 Jennifer C Zhao,2 Amer M Zeidan1,3 1Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT, USA; 2Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA; 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT, USACorrespondence: Amer M ZeidanSection of Hematology, Department of Internal Medicine, Yale University, 37 College Street, PO Box 208028, New Haven, CT 06520-8028, USATel +1 203-737-7103Fax +1 203-785-7232Email [email protected]: 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.Keywords: fedratinib, ruxolitinib, myelofibrosis, MF, JAK2
