Targeting the cytokine storm: new therapies in the treatment of pediatric hemophagocytic lymphohistiocytosis

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disorder characterized by immune hyper-activation and subsequent tissue and organ infiltration by proinflammatory cytokines. Primary HLH is caused by underlying genetic mutations in key genes responsible for cellular cytotoxicity, whereas secondary HLH is driven by infection, malignancy, and autoimmune disease as the underlying trigger for immune activation. Chemotherapy-based treatments for pediatric HLH have improved survival and outcomes for patients, however, there is a significant unmet need in the development of targeted therapies to limit drug toxicity and further improve overall survival. AREAS COVERED: We review primary and secondary HLH, current treatment strategies, and present rationale and available evidence for emerging targeted therapies for this orphan disease, including the human monoclonal anti-IFN‑γ antibody emapalumab, the anti-CD52 monoclonal antibody alemtuzumab, and the JAK1/2 inhibitor ruxolitinib, in the treatment of pediatric HLH. EXPERT OPINION: Development of targeted therapies in pediatric HLH is critical to improve survival and overall outcomes for these patients. Emapalumab, alemtuzumab, and ruxolitinib show promising results, however, widespread use is limited by small, non-randomized trials in a heterogenous population. Further international collaborative efforts to develop clinical trials that compare conventional chemotherapy treatments head-to-head with these newer therapies are critical for advancement of these agents.