HLHRUXO: A prospective trial of a ruxolitinib-containing regimen for children with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive immune cell activation and hypersecretion of inflammatory cytokines, many of which signal via the Janus kinases (JAKs). Preclinical studies have demonstrated that the JAK1/2 inhibitor ruxolitinib ameliorates disease manifestations and prolongs survival in mouse models of HLH. Similarly, clinical studies have suggested that ruxolitinib is safe and effective for children with HLH, although prospective trials evaluating optimal ruxolitinib doses in primary (i.e., inherited/genetic) HLH are lacking. To address this gap, we developed HLHRUXO (https://clinicaltrials.gov/study/NCT04551131), a prospective multi-institutional clinical trial utilizing a ruxolitinib-containing regimen in children with newly diagnosed or relapsed/refractory HLH. Patients received ruxolitinib 25 mg/m2 twice daily combined with dexamethasone, with or without etoposide, for eight weeks, followed by continuation therapy at the discretion of the treating physician. Pharmacokinetic studies were performed on days one and eight. Eight patients (average age 7.6 years; five primary HLH [pHLH] and three secondary HLH [sHLH]) completed the study; none experienced dose-limiting adverse events (AEs). All patients experienced a favorable response at one week, demonstrating clinical stabilization and improvement in serum ferritin levels. Further, all five patients (three pHLH, two sHLH) with newly diagnosed HLH achieved a complete response (CR) after eight weeks of treatment, and all were alive at one year. One patient with relapsed/refractory sHLH achieved a CR at eight weeks and was alive at one year, while two others with relapsed/refractory pHLH died. Our findings confirm the safety of this ruxolitinib-containing regimen for pediatric HLH, with the best results observed in patients with newly diagnosed disease. Further studies of ruxolitinib as frontline therapy for children with HLH are warranted.