The FREEDOM2 trial has demonstrated that fedratinib (Inrebic) is an effective second-line treatment option for patients with myelofibrosis who have previously been treated with ruxolitinib (Jakafi) but have either relapsed, are refractory, or are intolerant to it. The multicenter, open-label, randomized controlled trial showed a significant spleen volume reduction (SVR) in patients treated with fedratinib compared to those receiving best available therapy (BAT). The findings, published in The Lancet Haematology, highlight strategies for managing gastrointestinal adverse effects (AEs) and thiamine deficiency associated with fedratinib.
Key Findings from FREEDOM2
The FREEDOM2 study involved 201 patients with intermediate-2 or high-risk myelofibrosis who had previously been treated with ruxolitinib. Patients were randomized to receive either fedratinib (n = 134) or BAT (n = 67). The primary endpoint was the proportion of patients achieving an SVR of at least 35% (SVR35) at the end of cycle 6. The median follow-up was 64.5 weeks.
The results showed that 36% of patients in the fedratinib group achieved SVR35 compared to only 6% in the BAT group, representing a significant difference (30% difference; 95% CI, 20%-39%; 1-sided P < .0001).
Safety and Tolerability
While grade 3 or greater treatment-related AEs were more frequent in the fedratinib group (40%) compared to the BAT group (12%) during the first 6 cycles, the most common AEs, including anemia (9% in both arms) and thrombocytopenia (12% vs 3%), were manageable. Gastrointestinal AEs were also more frequent in the fedratinib group but were mostly grade 1 to 2 in severity and occurred primarily during the initial cycles. Notably, these gastrointestinal AEs were less frequent than those reported in previous clinical trials.
Thiamine Deficiency Management
The study also addressed the risk of thiamine deficiency associated with fedratinib. At baseline, 21% of patients in the fedratinib group had low thiamine levels, with only one additional case observed after the introduction of prophylactic thiamine supplementation. This suggests that proactive monitoring and supplementation can effectively mitigate this risk.
Clinical Implications
According to the study authors, "Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis."
The FREEDOM2 trial (NCT03952039) was conducted between September 9, 2019, and June 24, 2022.
