Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and Signal Transducer and Activation of Transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines. Here, we review the basic biology of HLH, including the role of cytokines in disease pathogenesis, and discuss the use of ruxolitinib in the treatment of HLH.

Keywords: Hemophagocytic lymphohistiocytosis; cytokine storm; inflammation; jak-stat; ruxolitinib.

Figure 1

Role of JAK/STAT signaling in fueling the fire of HLH. Here we show several of the cytokines that fuel the fire of HLH and their associated cellular sources. We also illustrate which of these cytokines bind to receptors associated with JAK-family kinases (JAK1, JAK2, JAK3, or TYK2) and are expressed on the surface of dendritic cells, CD4 and CD8 T cells, NK cells, neutrophils, monocytes, and macrophages. These JAK-dependent receptor-mediated signaling pathways represent potential targets of ruxolitinib. Note that many of the cytokines produced are also those that trigger cell activation and hence part of the feedforward loop. For simplicity, all receptors are drawn similarly, but it is noted that there exist some receptors that typically form complexes (e.g., GM-CSF), which are not depicted in this Figure. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLH, hemophagocytic lymphohistiocytosis; IFN-α/β, interferon alpha and beta; IFN-γ, interferon gamma; IL, interleukin; JAK, Janus kinase; NK cell, natural killer cell; TNF, tumor necrosis factor; TYK2, tyrosine-protein kinase 2.