A team of scientists led by researchers at St. Jude Children’s Research Hospital has revealed that the drug ruxolitinib helps counter some of the life-threatening effects of excessive inflammation in hemophagocytic lymphohistiocytosis (HLH). This family of related immune disorders is characterized by a massive accumulation and activation of white blood cells, such as T lymphocytes and macrophages, which produce large amounts of pro-inflammatory cytokines. A report on this study appears today in the journal Blood.
Patients with HLH often experience recurring bouts of immune activation leading to the onset of a “cytokine storm.” This extreme immune reaction contributes significantly to the morbidity and mortality associated with HLH. Currently, most patients with HLH are treated with a combination of immunosuppressive drugs such as steroids and chemotherapy. This approach is helpful in some patients. However, if the disease fails to respond to treatment, or if the condition relapses while a patient is undergoing therapy, few alternatives exist, and fatalities can reach 50 percent or higher. In this study, the scientists found that treatment with ruxolitinib, a drug that interferes with cytokine signaling, significantly diminished the inflammation associated with this disorder when tested in mouse model systems.
“Many of the key cytokines, such as interferon gamma, interleukin 6 and interleukin 2, which drive inflammation in hemophagocytic lymphohistiocytosis, bind to receptors that signal through the Janus kinase (or JAK) pathway. Since ruxolitinib is a potent inhibitor of JAK1 and JAK2, we decided to investigate its effects in hemophagocytic lymphohistiocytosis,” said Kim Nichols, M.D., a member of the St. Jude Department of Oncology and the study’s corresponding author. “We reasoned that inhibition of these JAKs might diminish inflammation and lessen disease.”
The scientists showed that the inhibition of JAK function with ruxolitinib, a commercially available drug, not only lessened inflammation but also led to the animals living longer. The researchers looked at two different systems – a mouse model of the non-inherited (also known as “secondary”) form of HLH and a model system of the inherited (or “primary”) form of the disorder. In the latter model, mice lacking expression of perforin (the protein defective in 20–30 percent of human patients with primary HLH), when infected with lymphocytic choriomeningitis virus, fail to clear the infection and develop cytokine storm. In both model systems, treatment with ruxolitinib decreased inflammation. As evidence of its positive effects, the drug also significantly improved the survival of virus-infected, perforin-deficient mice, with none of the ruxolitinib-treated mice dying. In contrast, all of the untreated mice succumbed to disease.
“Our results strongly suggest that the JAKs serve as novel, druggable targets for lessening the cytokine-driven hyperinflammation that occurs in patients with hemophagocytic lymphohistiocytosis,” Nichols said. Exposure to the drug limited the massive expansion of T cells linked to the disorder and reduced their production of pro-inflammatory cytokines.
Ruxolitinib has already been approved by the U.S. Food and Drug Administration for the treatment of other indications including high-risk myelofibrosis. The drug is undergoing evaluation in a number of other conditions, including childhood cancer. Since ruxolitinib has been well studied for many years, it is an attractive candidate for additional clinical trials in humans. “Our preclinical findings suggest that the integration of JAK inhibitors such as ruxolitinib into clinical trials for hemophagocytic lymphohistiocytosis may represent a viable strategy to counteract the damaging cytokine-driven tissue inflammation,” Nichols said. “It is our hope that by incorporating JAK inhibitors, we can improve the cure rate for children and adults suffering from this devastating and often life-threatening disorder.”
The study’s other authors are Rupali Das, Peng Guan, Leslee Sprague, Katherine Verbist, Paige Tedrick, Makoto Kurachi, Ross Levine, E. John Wherry, Scott W. Canna and Edward M. Behrens.
This research was supported by funding from Sean Fischel Connect; the National Institutes of Health (grant R21 AI113490; the Histiocytosis Association of America; and ALSAC.
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