Ruxolitinib (RUX), the original and first approved JAK1/2 inhibitor, and fedratinib (FEDR), a selective JAK2 inhibitor approved in 2019, exhibit improvements in symptoms and spleen response in some patients with myelofibrosis (MF). However, a high proportion of patients experience cytopenia and a diminished response to RUX over time, resulting in termination of RUX therapy. The current study report provides data on FEDR therapy in patients with MF.
FREEDOM, a phase 3b investigation, evaluated the safety and efficacy profiles of FEDR at a dose of 400 mg/day in patients previously treated with RUX. In the JAKARTA2 study, 31% of patients reached spleen volume response, defined as ≥35% spleen volume decrease from baseline to end of cycle 6, 27% experienced disease-related symptom response at an FEDR dose of 400 mg/day. Adverse events associated with FEDR in JAKARTA2 included primarily gastrointestinal issues and possible cases of Wernicke’s encephalopathy, which led to suspension of FEDR clinical use in 2013. Therefore, in addition to safety and efficacy, FREEDOM assessed the value of strategies to prevent or lessen adverse events due to FEDR, including Wernicke’s encephalopathy. Mitigation strategies included prophylactic and symptomatic treatment of nausea, vomiting and diarrhea, thiamine supplementation, FEDR dosing modifications, and administration of FEDR with food.
This study included 34 patients with a median age of 68.5 years (range, 49-82 years) and diagnosed with primary MF, or post-polycythemia vera MF, post-essential thrombocythemia MF, disease defined as intermediate or high risk (per Dynamic International Prognostic Scoring System), Eastern Cooperative Oncology Group performance status ≤2, platelet count ≥50 × 109/L, and spleen volume ≥450 mL or palpable spleen ≥5 cm below the left costal margin. Most patients had been diagnosed with primary MF (62%) and all had been previously treated with RUX for ≥3 months before discontinuation. Discontinuation of FEDR occurred for various reasons, including lack of benefit, high-grade or serious adverse events, disease progression, patient decision, and allogeneic transplant. Sixteen patients were treated with FEDR for a median duration of 28.3 weeks (range, 1.6-101.3 weeks). Reported grade 1 or 2 gastrointestinal adverse events included constipation (47%), diarrhea (35%), nausea (26%), abdominal pain (24%), and vomiting (18%). All adverse symptoms were reduced to 0% after 6 cycles of FEDR treatment. There were no grade 3 or 4 gastrointestinal adverse events associated with FEDR therapy. Non-gastrointestinal events included anemia, cytopenia, and hyperkalemia.
In conclusion, data from this phase 3 study suggest that FEDR is safe and effective in patients with myelofibrosis without neurologic or other types of severe adverse events. Mild gastrointestinal symptoms were managed with appropriate medications. Although there was no interruption of FEDR treatment due to low serum thiamine levels, some patients experienced a decrease in such levels below the lower limit of normal. There may be a benefit to checking thiamine levels before and during FEDR therapy.
Source: Gupta V, Yacoub A, Verstovsek S, et al. Safety and tolerability of fedratinib (FEDR), an oral inhibitor of Janus kinase 2 (JAK2), in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with ruxolitinib (RUX): results from the phase 3b FREEDOM trial. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 389.
