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

Camille Keenan,Sabrin Albeituni,Kim E Nichols

doi:10.3389/fimmu.2021.614704

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.

Highlights

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome resulting from inherited or acquired immune dysregulation
We demonstrated that ruxolitinib reversed many HLH manifestations, including splenomegaly, cytopenias, hypercytokinemias, peripheral organ and central nervous system (CNS) inflammation, and it significantly prolonged survival [39, 40]
Thanks to increased understanding of the roles played by cytokines in fueling the fire of HLH, studies of cytokine-targeting agents such as ruxolitinib have been initiated with emerging data suggesting that some of these agents, including ruxolitinib, represent potentially effective means to lessen inflammation in this disease

Summary

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome resulting from inherited (primary HLH) or acquired (secondary HLH) immune dysregulation. A recent report describes 27 patients with relapsed/refractory primary HLH treated with dexamethasone, the IFN-gamma neutralizing antibody emapalumab, and varying combinations of other agents [25].

Results

Conclusion