The Janus kinase (JAK) 1/2 inhibitor ruxolitinib may be more effective at treating hemophagocytic lymphohistiocytosis than drugs that inhibit only JAK1 or JAK2, according to a preclinical study published by Keenan et al in Blood. The disease’s inflammatory phenotype is known to be driven by the overproduction of cytokines that signal through the JAK/STAT pathway; the rare condition also has a 40% mortality rate. In the study, researchers examined the safety and efficacy of the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib, and the JAK1/2 inhibitor ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis. All three drugs suppressed interferon-gamma–induced STAT1 phosphorylation in vitro and in vivo. In CpG-induced secondary hemophagocytic lymphohistiocytosis, itacitinib—but not fedratinib—improved survival and clinical scores; whereas in primary hemophagocytic lymphohistiocytosis involving perforin-deficient mice infected with the lymphocytic choriomeningitis virus, both drugs were found to be suboptimal. The researchers revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, and fedratinib targeted cell proliferation and metabolism–regulating genes. Conversely, ruxolitinib demonstrated clinical efficacy in both primary and secondary hemophagocytic lymphohistiocytosis models, exerted significant transcriptional changes in CD8 T cells and monocytes, and targeted more genes across several biologic pathways—notably, JAK-dependent proinflammatory signaling. All three drugs were well tolerated. The researchers will further analyze the efficacy of ruxolitinib in combination with the steroid dexamethasone in an ongoing clinical trial for pediatric patients with hemophagocytic lymphohistiocytosis called HLHRUXO. In a companion press release on the findings from the St. Jude Children’s Research Hospital, the study authors concluded: “We showed ruxolitinib is a safe and potentially more effective therapy for [hemophagocytic lymphohistiocytosis] than the current standard of care.”