An update in the diagnosis and therapy of hemophagocytic lymphohistiocytosis

Primary hemophagocytic lymphohistiocytosis (pHLH) is a fatal, autosomal recessive hyperinflammatory syndrome. Infections, neoplasia, and underlying autoimmune and autoinflammatory conditions trigger secondary HLH. In pHLH, immunosuppression with dexamethasone and etoposide has been used as the standard of care before hematopoietic transplantation, the only curative option. However, approximately one-third of the patients do not achieve remission and die before transplantation. As a result, the focus has shifted to novel biologic agents and we discuss these here. Emapalumab (Gamifant®, a monoclonal antibody that neutralizes free and receptor-bound interferon-γ), has been approved in the US for HLH since 2020 based on its efficacy in 34 patients. The European Medicines Agency has refused marketing authorization, expressing concerns regarding its efficacy, since most responding patients required additional therapy. As the JAK/STAT pathway is critical for cytokine signaling and has a significant role in HLH, its suppression by ruxolitinib (Jakafi®, a potent anti-inflammatory inhibitor) has been successful in animal models of HLH. Over the last 6 years, several clinical studies, mainly from China, have studied ruxolitinib's use in HLH. All have shown ruxolitinib to be safe and effective, minimizing or avoiding exposure to chemotherapy. Beyond emapalumab and ruxolitinib, other agents have shown promise in managing aspects of HLH, including interleukin-1 receptor antagonists, such as anakinra, tocilizumab (Actemra®, a recombinant humanized monoclonal antibody against the interleukin-6 receptor), alemtuzumab (Campath® and Lemtrada®, a monoclonal antibody against CD52), and finally, tadekinig alpha, a recombinant interleukin-18 binding protein with a high affinity for IL-18, a major inflammatory cytokine. In summary, a growing number of biological agents are expected to play a key role in the treatment of HLH in the immediate future.