Results from FREEDOM Indicate Fedratinib Is Effective and Safe in Patients with Myelofibrosis Previously Treated with Ruxolitinib

Myelofibrosis (MF) is a cancer of the bone marrow characterized by an enlarged spleen, scarring, and anemia. Ruxolitinib (RUX), a JAK1/2 inhibitor, has demonstrated efficacy in patients with MF. However, a high proportion of patients experience cytopenia and a diminished response to RUX over time, resulting in termination of RUX therapy. Fedratinib (FEDR) is a selective JAK2 inhibitor recently approved in 2019 to treat MF.

The current phase 3b investigation, FREEDOM, examines the safety and efficacy of 400 mg/day of FEDR in patients previously treated with RUX. In a previous clinical trial, JAKARTA2, 31% of patients achieved spleen volume response and 27% had systemic volume response at the 400-mg/day dose. Due to prior reports of gastrointestinal (GI) issues and possible cases of Wernicke’s encephalopathy, FREEDOM also aims to evaluate effectiveness of strategies devised to prevent or lessen adverse events and 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.

FREEDOM included 34 patients with a median age 68.5 years (range, 49-82 years) and Dynamic International Prognostic Scoring System–defined as intermediate- or high-risk, diagnosed with primary MF, or post-polycythemia vera MF, post-essential thrombocythemia MF, Eastern Cooperative Oncology Group performance status ≤2, platelet count ≥50 ×10⁹/L, and spleen volume ≥450 cm³ or palpable spleen ≥5 cm below the left costal margin. The majority of 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 no benefit to therapy, adverse events, disease progression, patient decision, and 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 GI 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 GI adverse events associated with FEDR therapy. Non-GI events included anemia, cytopenia, and hyperkalemia.

No cases of Wernicke’s encephalopathy or severe adverse events were reported from FREEDOM. The mild GI symptoms were alleviated with appropriate GI medications. Although there was no interruption of FEDR treatment due to thiamine levels, some patients experienced a drop below lower limit of normal, which suggests the potential need for monitoring thiamine before and during FEDR therapy. Overall, the results suggest FEDR is effective and well-tolerated in patients with primary MF.

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.