Comparative efficacy and safety of JAK inhibitor-based strategies in JAK inhibitor-naïve myelofibrosis: A systematic review and network meta-analysis
In brief
Ruxolitinib combinations more than tripled odds of major spleen shrinkage
In a review of seven trials involving 2,254 JAK inhibitor-naive patients, ruxolitinib combinations more than tripled the odds of a 35% or greater spleen-volume reduction at 24 weeks compared with ruxolitinib alone, but did not improve symptom response. Other drugs had different safety advantages, including less anemia with momelotinib; indirect comparisons leave the best first-line choice dependent on patients' priorities and risks.
- Journal
- Therapeutic advances in hematology (Q1)
- Published
- 2 September 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Zhongwang Wang, Linfeng Li, Ting Niu, He Li
- PMID
- 42851825
- DOI
- 10.1177/20406207261484707
Why clinicians should know about it
- Picked for Hematology (top studies of the week, 11 October 2026): JAKi combos improve splenic response; safety profiles guide MF first-line
Abstract
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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.