According to the phase 3 randomized FREEDOM2 trial, Janus kinase inhibitor (JAKi) fedratinib, demonstrated spleen volume reduction (SVR) and symptom reduction versus treatment with the best available therapy (BAT) among patients with myelofibrosis (MF) previously treated with ruxolitinib.

These results will be presented by Haifa Kathrin Al-Ali, MD; PhD, Universitätsklinikum Halle, Saale, Germany, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

“Low platelet count (PLT; <100 x 10⁹/L) is associated with inferior survival in MF, and thrombocytopenia can result in JAKi dose reductions/interruptions,” explained Al-Ali and colleagues.

 A pooled analysis of the JAKARTA and JAKARTA2 trials indicated efficacy of fedratinib among patients with low baseline (BL) PLT. Additionally, exploratory FREEDOM2 subgroup analyses showed a trend towards enhanced SVR in pts with low BL PLT. The FREEDOM2 subanalysis continued to examined the impact of fedratinib on platelet levels, efficacy, and safety in patients with low (50-<100 x 10⁹/L) vs high (≥100 x 10⁹/L) BL PLT.

In this trial adult patients with intermediate-2 or high-risk MF relapsed/refractory or intolerant to ruxolitinib were randomized 2:1 to receive fedratinib 400 mg once daily or BAT, which was 78% ruxolitinib, while patients with BL PLT <50 x 10⁹/L were excluded. They were treated until intolerance or lack of efficacy and followed up every 3 months. The primary end point was ≥35% SVR (SVR35) at the end of cycle 6 (EOC6). Hematology assessments were at screening, days 1 and 15 of cycles 1 to 3, day 1 of each subsequent cycle up to end of treatment, and at 30-day follow-up.

At the data cutoff of May 10, 2023, pts receiving fedratinib displayed significantly higher rates of SVR35 at EOC6 vs BAT with low (47% vs 0%, P = 0.0001) and high (35% vs 10%, P = 0.0043) PLT. Among evaluable pts, rates of total symptom score reduction ≥50% at EOC6 were also higher among pts treated with fedratinib vs BAT in pts with low (38% vs 20%, P = 0.2280) and high (36% vs 16%, P = 0.0304) PLT.

As for treatment-related adverse events, during the first 6 cycles, rates of grade 3 or 4 hematologic treatment-emergent adverse events were highest among pts with low BL PLT treated with fedratinib compared with other groups (low PLT: fedratinib 76% vs BAT 57%; high PLT: fedratinib 61% vs BAT 33%). The most frequently noted grade 3 or 4 events were thrombocytopenia (low PLT: fedratinib 29% vs BAT 10%; high PLT: fedratinib11% vs BAT 0%) and anemia (low PLT: fedratinib 18% vs BAT 24%; high PLT: fedratinib 27% vs BAT 13%). Study authors noted thrombocytopenia as the most frequent cause of treatment-related dose reduction (low PLT: fedratinib 18% vs BAT 5%; high PLT: fedratinib 2% vs BAT 3%). Treatment discontinuation rates resulting from adverse events were higher in pts treated with fedratinib vs BAT (low PLT: fedratinib 12% vs BAT 5%; high PLT: fedratinib 9% vs BAT 5%); only 1 pt discontinued fedratinib due to thrombocytopenia (pt with low BL PLT).

The patients treated with fedratinib showed early increases in PLT versus BAT, with a greater magnitude of increase among patients with low vs high BL PLT. Increased PLT did not correlate with spleen size change, indicating a potentially beneficial effect of fedratinib on thrombopoiesis. SVR35 rates were numerically higher in pts with low versus high BL PLT treated with fedratinib. They found that safety aligned with previous trials.

“Together, these data suggest a platelet sparing effect of second-line fedratinibb vs best-available therapy, and support fedratinibatinib as a promising second-line treatment option for patients with myelofibrosis with low or high BL PLT,” concluded Al-Ali and coauthors.

Source:

Al-Ali H, Harrison C, Mesa R, et al. Efficacy and Safety of Fedratinib in Patients with Myelofibrosis and Low Baseline Platelet Counts in the Phase 3 Randomized FREEDOM2 Trial. Presented at 2024 ASH Annual Meeting & Exposition. Dec 7-10, 2024; San Diego, CA. Abstract: 482