Differential efficacy and safety of ruxolitinib in primary versus secondary hemophagocytic lymphohistiocytosis: a systematic review and meta-analysis

Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, has demonstrated therapeutic potential in both primary and secondary hemophagocytic lymphohistiocytosis (pHLH & sHLH), but quantitative evidence comparing its efficacy and safety across subtypes remains lacking. Given the absence of randomized controlled trials evaluating RUX in HLH, we conducted a systematic review and single-arm meta-analysis to assess RUX-based regimens. Eighty-three studies comprising 542 patients were included, of which 27 were single-arm trials or cohort studies and 56 were case reports/series. The pooled overall response (OR) rate was 87.2% (95% CI, 80.8–92.7%; I 2 = 55.0%), with pHLH achieving 100% versus 82.4% in sHLH ( p = 0.005). Overall survival (OS) rates were 91.6% at 2 months (95% CI, 85.1% to 96.7%; I 2 = 37.8%), 81.6% at 6 months (95% CI, 69.5% to 91.7%; I 2 = 66.5%), and 73.9% at 1 year (95% CI, 56.3% to 88.9%; I 2 = 76.9%); pHLH demonstrated superior 2-month survival compared to sHLH (100% vs. 87.7%, p = 0.005). These findings remained robust in sensitivity analyses excluding case reports. The most frequent adverse events were infections (9.3%), neutropenia (7.5%), and hepatic dysfunction (7.0%), with higher rates of pancreatic injury and severe hematological toxicities in pHLH. This largest evidence synthesis to date supports the efficacy of RUX-based regimens in HLH, with higher pooled short-term response estimate in pHLH than in sHLH. Despite inherent limitations of rare disease research, these findings provide critical guidance for clinical practice and future trial design. PROSPERO (CRD42025639580).