Hemophagocytic Lymphohistiocytosis: Its Biochemical Basis and Clinical Implications

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive cytokine activation. Its treatment remains extremely limited, with high mortality. Recent research into its pathogenesis has revealed the major role of cytokines, such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha, interleukin-1 (IL-1), IL-6, and IL-18. These cytokines may also help identify HLH in the early stage or predict HLH in high-risk patients in the future. Both animal and human research provide evidence of the role of biochemical mediators in HLH. In addition, the interplay between cytokines and cells in the pathogenesis of HLH has opened up new targeted therapeutics. These treatment alternatives are being tried for the primary and secondary forms of HLH, with promising results. Emapalumab, an anti-IFN-γ monoclonal antibody, has been widely studied in HLH with favorable results. Anti-IL-1 receptor antibody (anakinra), anti-IL-18 neutralizing molecule (tadekinig-α), and anti-CD52 monoclonal antibody (alemtuzumab) are among the newer drugs in the pipeline for the treatment of HLH. Small molecule inhibition beyond receptor activation in cells has previously had immense success in treating spondylarthritis and leukemia. Ruxolitinib, a Janus kinase inhibitor, also demonstrated positive outcomes in HLH treatment. With these emerging treatment options, the future outlook for HLH is moving toward a promising new horizon.