Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, 
hyperinflammatory disorder, characterized by uncontrolled activation of the 
immune system. Mutations affecting several genes coding for proteins involved in 
the cytotoxicity machinery of both natural killer (NK) and T cells have been 
found to be responsible for the development of pHLH. So far, front-line 
treatment, established on the results of large international trials, is based on 
the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic 
hematopoietic stem cell transplantation (HSCT), the sole curative treatment for 
the genetic forms of the disease. However, despite major efforts to improve the 
outcome of pHLH, many patients still experience unfavorable outcomes, as well as 
severe toxicities; moreover, treatment-refractory or relapsing disease is a 
major challenge for pediatricians/hematologists. In this article, we review the 
epidemiology, etiology and pathophysiology of pHLH, with a particular focus on 
different cytokines at the origin of the disease. The central role of 
interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is 
analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody 
is discussed. Available data support the use of emapalumab for treatment of pHLH 
patients with refractory, recurrent or progressive disease, or intolerance to 
conventional therapy, recently, leading to FDA approval of the drug for these 
indications. Additional data are needed to define the role of emapalumab in 
front-line treatment or in combination with other drugs.