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.

Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial

“…18 Ruxolitinib reduces concentrations of inflammatory cytokines in disorders in which cytokine dysregulation plays a role, including graft-versus-host disease 19 and hemophagocytic lymphohistiocytosis. 20 , 21 , 22 …”

Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma

“…This amelioration is linked to the suppression of several chemokines, cytokines, and downstream inflammatory mediators that drive asthma pathogenesis in steroid-unresponsive patients. Ruxolitinib is a potent, highly bioavailable JAK1/2 inhibitor that is already US Food and Drug Administration (FDA) approved for the treatment of myelofibrosis, polycythemia vera, steroid-refractory acute graft versus host diseases and atopic dermatitis (84). Importantly, Ruxolitinib targets inflammation differently than steroids, and thus, it can be used independently or in combination with steroids to treat severe asthmatics more effectively.…”

Neuroinflammation Associated With Inborn Errors of Immunity

“…Although neutralization of specific cytokines such as TNF and IL-1 have been used as second line treatment for HLH, their efficacy is unknown. Novel treatment strategies that are being pursued include anti-IFN-γ and JAK-inhibition ( 212 , 213 ).…”