Efficacy and safety of ruxolitinib-based combination therapy in the patients with myelofibrosis (MF): A systematic review and meta-analysis

Abstract

Abstract ABSTRACT Background: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, anemia, bone marrow fibrosis, and a constellation of debilitating systemic symptoms. It is associated with significant morbidity and mortality. Although ruxolitinib, a JAK1/2 inhibitor, remains the cornerstone of MF treatment, it does not reverse disease progression, and resistance frequently emerges. These limitations have prompted investigation into combination therapies targeting pathways beyond the JAK-STAT axis. This meta-analysis aims to evaluate the efficacy and safety of ruxolitinib-based combination therapies in patients with MF. Methods: We conducted a systematic search of PubMed, EMBASE, the Cochrane Library, and additional databases for studies published through June, 2025. Thirteen distinct ruxolitinib-based combination regimens were included. Primary efficacy endpoints were ≥35% spleen volume reduction at 24 weeks (SVR35) and ≥50% reduction in total symptom score (TSS50). Safety endpoints focused on the incidence of grade 3/4 thrombocytopenia and anemia. Subgroup analyses were performed based on prior JAK inhibitor exposure and therapeutic mechanism of action. Meta-analyses were conducted using RevMan 5.4, with 95% confidence intervals (CI) reported. Results: A total of 19 studies comprising 1,088 patients were included in the meta-analysis. The pooled rates of SVR35 and TSS50 were 50% (95% CI: 37–64%) and 39% (95% CI: 28–49%), respectively. Among JAK inhibitor-naïve patients, the combination of ruxolitinib with selinexor demonstrated the highest efficacy (SVR35: 92%; TSS50: 78%), followed by ruxolitinib plus BMS-986158 (SVR35: 90%). In addition, the efficacy ofthe combination of ruxolitinib with IFNα(SVR35:70%) and pelabresib (SVR35:66%; TSS50:53%) are also acceptable. For patients with prior JAK inhibitor exposure, ruxolitinib plus siremadlin (SVR35: 45%) and ruxolitinib plus selinexor (SVR35: 38%; TSS50: 33%) showed notable activity. Mechanism-based subgroup analysis revealed that XPO1 inhibitors combined with ruxolitinib yielded pooled SVR35 and TSS50 rates of 65% and 54%, respectively, while BET inhibitors achieved 60% and 49%, respectively. Reported rates of grade 3/4 adverse events were 26% for thrombocytopenia, 31% for anemia, and 19% for neutropenia. Conclusion: For JAK inhibitor-naïve patients, ruxolitinib-based combination regimens demonstrated advantages over ruxolitinib monotherapy. For patients with prior JAK inhibitor exposure, the addition of combination therapy drugs may further enhance the efficacy. Personalized treatment selection remains essential, as therapeutic efficacy is significantly influenced by prior JAK inhibitor exposure. KEY WORDS: Ruxolitinib, Myelofibrosis (MF), Meta-analysis, Combination therapy, Systematic review