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 shown preliminary evidence of efficacy for treatment of HLH in children; however, prospective trials evaluating optimal ruxolitinib doses in HLH in pediatric are lacking. To address this gap, we developed HLHRUXO, a prospective clinical trial using a ruxolitinib-containing regimen for children with HLH. Patients received ruxolitinib 25 mg/m2 twice daily combined with dexamethasone, with or without etoposide, for 8 weeks, followed by continuation therapy at the discretion of the treating physician. Pharmacokinetic studies were performed on days 1 and 8. A total of 8 patients (average age, 7.6 years; 5 with primary HLH pHLH], and 3 with secondary HLH [sHLH]) completed the study; no patients experienced dose-limiting adverse events. All patients experienced a favorable response at 1 week, demonstrating clinical stabilization and improvement in serum ferritin levels. Furthermore, all 5 patients with newly diagnosed HLH (3 with pHLH, 2 with sHLH) achieved a complete response (CR) by 8 weeks, and all were alive at 1 year. One patient with relapsed/refractory sHLH achieved a CR at 8 weeks and was alive at 1 year, whereas 2 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. This trial was registered at www.clinicaltrials.gov as NCT04551131.