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FREEDOM Trial Finds Fedratinib Well Tolerated in MF; Offers Strategies To Mitigate GI AEs
Results of the ongoing, single-arm phase 3b FREEDOM trial were shared at the 2021 American Society of Hematology (ASH) Annual Meeting, and highlight the safety and efficacy of fedratinib in patients with myelofibrosis (MF) previously treated with ruxolitinib.
“Unlike JAKARTA2 and other early fedratinib trials, FREEDOM includes prospective strategies for preventing or mitigating gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential Wernicke’s encephalopathy (WE) cases,” explained Vikas Gupta, MD, FRCP, FRCPath, Princess Margaret Cancer Center, Canada, and co-investigators.
In this trial, researchers aimed to determine the safety of fedratinib 400 mg per day, as well as the effectiveness of the strategies.
Patients eligible for enrollment were required to be older than 18 years of age with Dynamic International Prognostic Scoring System (DIPSS)-defined intermediate- or high-risk, primary or post-polycythemia vera (PV)/essential thrombocythemia (ET) MF, had an ECOG PS ≤ 2, platelet count ≥ 50 ×109/L, and had spleen volume ≥ 450 cm3 by MRI/CT or palpable spleen ≥ 5 cm below the left costal margin (LCM).
Further, patients were required to have prior treatment history of ruxolitinib for ≥ 3 months, or for 28 days with development of red blood cell (RBC) transfusion requirement or grade ≥ 3 thrombocytopenia, anemia, hematoma, or hemorrhage. All patients enrolled received fedratinib 400 mg once daily in continuous 28-day cycles.
“AE mitigation strategies included prophylactic and symptomatic use of anti-nausea/vomiting and anti-diarrheal treatment, thiamine supplementation, fedratinib dosing modifications, and administration of fedratinib with food,” continued Dr Gupta and co-authors.
All patients who received at least 1 dose of fedratinib were evaluated for safety.
In total, 34 patients with MF were enrolled and 16 continued to receive fedratinib after the data cutoff of April 2021. Reasons for fedratinib treatment discontinuation included lack of efficacy (n=5), AEs (n=4), patient decision (n=2), and to undergo transplant (n=2). The median fedratinib treatment duration was 28.3 weeks (range 1.6-101.3); 20 patients (59%) received > 6 treatment cycles and 14 patients (41%) completed > 12 cycles.
Baseline characteristics identified in the cohort included the median age of patients was 68.5 years (49-82), time from MF diagnosis was 3.4 years (0.1-17.4), and spleen size was 15 cm (3-31). Most patients (62%) were reported to have primary MF. The most common reason for prior ruxolitinib discontinuation was loss of response and treatment failure (41%).
“During fedratinib treatment, 22 patients (65%) received ondansetron and 11 (32%) received loperamide. GI AEs reported in > 10% of patients were constipation (47%), diarrhea (35%), nausea (26%), abdominal pain (24%), and vomiting (18%). The frequency of these AEs decreased as treatment continued,” said Dr Gupta and co-investigators.
Most GI AEs were grade 1 or 2. Overall, Treatment-related grade 3 or 4 AEs were reported in 11 patients (32%) and included anemia in 7 patients (21%); and neutropenia, thrombocytopenia, and hyperkalemia in 2 patients each (6%). There were no WE cases identified.
“Fedratinib was generally well tolerated. These data suggest the frequency and severity of GI AEs may be reduced via early implementation of GI prophylaxis. Use of GI-directed therapies may have increased the incidence of low-grade constipation. Monitoring thiamine levels before fedratinib initiation and periodically during fedratinib therapy is recommended,” concluded Dr Gupta, et al.—Alexa Stoia
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. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 389.
