FREEDOM2: Researchers Explore Safety and Efficacy of Fedratinib in Ruxolitinib-Pretreated Myelofibrosis

Treatment with the JAK2/FLT3 inhibitor fedratinib showed promise as a second-line therapy for patients with ruxolitinib-pretreated myelofibrosis, according to data from the FREEDOM2 trial reported by Claire N. Harrison, DM, of Guy’s and Thomas’ NHS Foundation Trust in London, UK, and colleagues. These findings were published in The Lancet Haematology.

Most patients with myelofibrosis develop ruxolitinib intolerance or relapsed or refractory disease and have a median survival of 11 to 14 months after discontinuation. In previous studies, fedratinib led to spleen improvements and symptom responses as well as gastrointestinal (GI) adverse events (AEs) and thiamine deficiency requiring mitigation. FREEDOM2 evaluated the use of fedratinib, along with prophylaxis for GI AEs and thiamine, to address poor outcomes after ruxolitinib failure.

The multicenter, open-label, randomized phase 3 trial (NCT03952039) was conducted at 86 sites across 16 countries from September 2019 to June 2022. Eligible participants were aged 18 years and older with intermediate-2 or high-risk myelofibrosis as defined by the Dynamic International Prognostic Scoring System (DIPSS), and they had experienced a relapse, refractory disease, or intolerance to prior therapy with ruxolitinib. Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, platelet count of at least 50×10⁹/L, spleen volume of at least 450 cm³, and normal baseline thiamine levels. Randomization was stratified by spleen size, platelet count, and prior ruxolitinib treatment history.

In the experimental arm, patients received 400 mg of oral fedratinib daily, and those in the control arm received investigator’s choice of best available therapy (BAT). In 65% of cases, BAT was ruxolitinib. Of 316 patients screened, 201 were randomized to fedratinib (n=134) or BAT (n=67). Patients had a median age of 68 years, 59% were men, and 91% had intermediate-2 risk disease. The median duration of prior ruxolitinib therapy was 25 months. Crossover from BAT to fedratinib was permitted after the end of cycle 6 or on disease progression, and 46 patients crossed over.

At the end of cycle 6, 36% of patients treated with fedratinib achieved spleen volume reduction of at least 35% versus 6% treated with BAT (difference, 30%; 95% CI, 20%-39%; P <0.0001). Total symptom score reduction of at least 50% was achieved by 34% of patients treated with fedratinib versus 10% treated with BAT (P =0.0003). Spleen volume reduction of at least 25% was achieved by 47% of patients treated with fedratinib versus 9% treated with BAT (P<0.0001). Median response duration was not reached.

Grade 3/4 adverse events occurred in 80% of patients treated with fedratinib versus 26% treated with BAT; AEs included anemia (34% vs 22%) and thrombocytopenia (22% vs 9%). Patients received prophylactic antiemetics and phosphate binders for potential GI side effects in addition to thiamine supplementation and monitoring to prevent deficiency. Gastrointestinal adverse events (diarrhea, 62% vs 15%; nausea, 40% vs 9%; vomiting, 37% vs 6%) were mostly grade 1/2 and occurred early in the course of treatment. Low thiamine levels occurred in 21% of patients treated with fedratinib versus 4% treated with BAT, with one case occurring after prophylaxis. No Wernicke encephalopathy was reported. Discontinuations occurred in 48% of patients treated with fedratinib (19% due to adverse events) versus 70% treated with BAT (58% due to progression). Deaths occurred in 12% of patients treated with fedratinib versus 10% treated with BAT; none were considered treatment related.

These findings support fedratinib as an option to “reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis, and shows effective strategies for management of gastrointestinal adverse events and low thiamine concentrations through prophylaxis, monitoring, and treatment,” the authors concluded.

Ongoing research is required to assess long-term survival outcomes and biomarkers.