Pathophysiology and treatment strategies in malignancy-induced HLH. HMs are known to secrete cytokines (IL-6, IL-10, IFN-γ), which are able to further drive cell division and prevent the organized recruitment of CD8 T cells to the tumor microenvironment (A). These T cells and accompanying NK cells then secrete IL-2, further increasing the burden of cells, which are unable to effectively remove HM. In addition, cell turnover and cytokine production drives downstream activation of macrophages. Together, these components combine to create HLH, resulting in cytokine-driven cytopenias, hyperferritinemia, splenomegaly, and end-organ damage. To treat HLH, specific treatments to prevent T-cell recruitment, reproduction, and cytokine secretion are being used (B). The treatment regimen using etoposide, antithymocyte immunoglobulin, and cyclosporine includes the most broad approach and has demonstrated efficacy. More specific treatments are now in trial, including the anti-IFN-γ antibody, NI-0501. Approaches to alleviate activation of JAK1/2 using ruxolitinib and IL-6 secretion (tocilizumab) are also in trial. Several other agents are routinely used, including infliximab and anakinra, but are not consistently shown to demonstrate efficacy. NF-κB using rosiglitazone is also a potential target, but potentially complicated because of the wide-reaching effects of a blockade.