Efficacy of ruxolitinib in hemophagocytic lymphohistiocytosis (HLH): a systematic review and meta-analysis

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by severe hypercytokinemia and multi-organ failure. Standard first-line regimens, such as the HLH-94/2004 protocols incorporating etoposide and dexamethasone, carry substantial toxicities and are associated with high rates of refractory or relapsing disease. Ruxolitinib, an oral Janus kinase (JAK) 1/2 inhibitor, has emerged as a promising targeted therapeutic agent capable of dampening the foundational cytokine storm (particularly interferon-gamma signaling) driving HLH pathogenesis. However, compiled evidence evaluating its definitive efficacy across broader clinical cohorts remains limited. This systematic review and meta-analysis aims to evaluate the overall clinical response rate of ruxolitinib in patients with HLH.

A systematic literature search was conducted across PubMed, ClinicalTrials.gov, Cochrane, and EMBASE to identify prospective or retrospective clinical studies reporting the efficacy of ruxolitinib in patients diagnosed with HLH. The primary endpoint evaluated was the overall clinical response rate (ORR). Statistical pooling was performed using a random-effects model with the inverse variance method. Proportions were stabilized using the Freeman-Tukey double arcsine transformation to manage variance. Heterogeneity across the included studies was quantified using the I2 statistic and the Q test.

A total of 17 prospective and retrospective studies published between 2019 and 2026 were included in the final analysis, encompassing an aggregate cohort of 397 patients with HLH. The meta-analysis revealed a highly encouraging pooled overall response rate. The overall pooled ORR was 82% (95% CI: 76%-88%), demonstrating a consistently high therapeutic response across cohorts. The calculated prediction interval ranged from 61% to 97%, indicating a favorable response likelihood in future clinical settings. Heterogeneity was moderate (I2=47.3%, p=0.0162), reflecting clinical variations in patient age, underlying HLH etiologies (e.g., familial, malignancy-associated, or infection-triggered), and different therapeutic combinations.

This meta-analysis demonstrates that ruxolitinib exhibits robust clinical efficacy in patients with HLH, yielding an overall response rate exceeding 80%. These findings support the integration of JAK1/2 inhibition into salvage regimens for refractory disease or potentially as part of front-line, steroid-sparing strategies to minimize traditional chemotherapy-related toxicities. Given the observed heterogeneity across the literature, prospective randomized controlled trials are warranted to optimize the optimal dosing, timing, and combination strategies for ruxolitinib in distinct clinical subgroups of HLH.