Comparative efficacy and safety of JAK inhibitor-based strategies in JAK inhibitor-naïve myelofibrosis: A systematic review and network meta-analysis

Background Myelofibrosis is a debilitating neoplasm with progressive bone marrow fibrosis, splenomegaly, and leukemic transformation risk. While ruxolitinib remains the standard for intermediate/high-risk MF, new strategies, including novel JAK inhibitors and ruxolitinib-based combinations, aim to improve efficacy and safety. However, direct comparisons of these strategies in JAK inhibitor-naïve patients remain limited. Objectives To compare the efficacy and safety of ruxolitinib, novel inhibitors, and combinations in JAKi-naïve MF. Design A systematic review and network meta-analysis of RCTs. Data Sources and Methods We searched electronic databases through November 2025 for RCTs evaluating JAK inhibitors in JAKi-naïve MF. The efficacy endpoints were spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50) at week 24. Safety outcomes included adverse events (AEs) as well as treatment discontinuation rates. Results Seven RCTs (n=2,254) were analyzed. Ruxolitinib combinations significantly improved SVR35 over ruxolitinib (OR = 3.63) but not TSS50. Momelotinib showed comparable SVR35 (OR = 0.886), while selective JAK2 inhibitors (fedratinib and pacritinib) were numerically inferior in efficacy. Regarding safety, fedratinib had the lowest risk of grade ≥3 thrombocytopenia (OR = 0.204); pacritinib, the lowest risk of all-grade thrombocytopenia (OR = 0.209); momelotinib, the lowest risk of all-grade anemia (OR = 0.226) and grade ≥3 anemia (OR=0.187). JAK2 inhibitors significantly increased diarrhea risk (OR=6.19). Notably, ruxolitinib monotherapy maintained the lowest AEs-related discontinuation rates in patients with platelets ≥ 50×10^9/L. Conclusion In first-line therapy, our findings support a stratified approach. Ruxolitinib combinations are preferred for patients where maximal splenic debulking is the primary goal. Selective JAK2 inhibitors provide a safe option for patients with profound thrombocytopenia. Momelotinib matches ruxolitinib’s efficacy via JAK1/2 inhibition while being optimal for baseline anemia via ACVR1 inhibition. Crucially, ruxolitinib remains the benchmark for symptom control and treatment retention in patients with adequate platelets. Registration CRD420261330640.