JAK inhibitors after ruxolitinib failure in MF

Results from a systematic review and pooled analysis evaluating the efficacy and safety of three Janus kinase inhibitors (JAKi: fedratinib, momelotinib, and pacritinib) in adults with myelofibrosis (MF) after ruxolitinib failure were published in the British Journal of Haematology by Duminuco et al. In the efficacy analysis, outcomes were drawn from prospective phase III or pivotal phase II trials, while safety data were taken from pivotal phase III trials, supporting phase II/IIIb trials, and real-world cohorts. The primary endpoint was ≥35% reduction in spleen volume from baseline (SVR35) at Week 24.

Key data: Pooled SVR35 at Week 24 was 32.7% (95% confidence interval [CI], 27.3–38.6; n = 266) for fedratinib, 15.8% (95% CI, 11.7–21.0; n = 234) for momelotinib, and 21.6% (95% CI, 13.8–32.3; n = 74) for pacritinib. SVR35 was significantly greater with fedratinib vs momelotinib (relative risk [RR], 2.07; 95% CI, 1.45–2.95; p < 0.0001) and was numerically greater than with pacritinib (RR, 1.51; 95% CI, 0.97–2.36; p = 0.08). Pooled ≥50% Total Symptom Score (TSS50) reduction rates were 32.8%, 25.3%, and 32.4% in the fedratinib, momelotinib, and pacritinib groups, respectively. Across an integrated safety dataset (n = 1,794), fedratinib showed the highest Grade ≥3 anemia (34.3% vs 21.2% and 8.0%, respectively) and any-grade diarrhea rate (56.6% vs 41.9% and 21.2%, respectively) vs pacritinib and momelotinib. Rates of Grade ≥3 thrombocytopenia were greatest with pacritinib (32.5%), followed by fedratinib (17.2%) and momelotinib (12.9%). Discontinuations due to adverse events (AEs) were comparable across agents (~15%–16%).

Key learning: In this pooled analysis, post-ruxolitinib JAKi demonstrate distinct efficacy and safety profiles, supporting treatment selection guided by clinical phenotypes.