Ruxolitinib, a JAK1/JAK2 Selective Inhibitor, Ameliorates Gastrointestinal and Cutaneous Pathogenesis in MHC-Mismatched Preclinical Models of Acute and Chronic Graft-Versus-Host Disease

Abstract

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is potentially curative for a variety of hematologic malignancies. However, rather than targeting tumor cells, alloreactive donor T cells may attack healthy recipient tissue triggering graft-versus-host disease (GVHD) resulting in morbidity and mortality. Acute GVHD (aGVHD) clinically presents with gastrointestinal (GI) pathology and is primarily T cell mediated. In contrast, chronic GVHD commonly demonstrates skin inflammation and fibrosis with an autoimmune-like phenotype. Pharmacological inhibition of JAK/STAT signaling has the potential to regulate aberrant immune cell functions involved in the pathogenesis of acute and chronic GVHD. Aim: Characterize the effectiveness of ruxolitinib to modulate in vitro and in vivo immunological mechanisms that are described to be critical in acute and chronic GVHD pathogenesis. Materials and Methods: MHC-mismatch aGVHD was induced in recipient BALB/c mice receiving C57BL/6 donor transplant. Sclerodermatous cGVHD was induced in C57BL/6 mice using LP/J strain donor splenocytes and bone marrow cells. Ruxolitinib or vehicle was orally administered twice daily. Efficacy was assessed by GVHD symptom scores, cachexia, and histological analysis of end organ damage. Mixed lymphocyte reactions (MLR) were cultured for five days in the presence of ruxolitinib for changes in activation markers and cytokine release. Results: Ruxolitinib treatment ameliorated daily aGVHD severity scores with concomitant reduction of GI tract infiltration and tissue damage. Overall aGVHD mice survival was significantly improved with JAK1/2 inhibition. Therapeutic ruxolitinib treatment initiated after cGVHD symptom onset significantly inhibited the chronic-progressive symptom phenotype and reduced tissue markers of inflammation and fibrosis. Ruxolitinib demonstrated concentration-dependent inhibition of activated T cells and reduced JAK-STAT signaling cytokines considered relevant in GVHD inflammation. Conclusion: Ruxolitinib, a potent and selective JAK1/2 inhibitor, significantly ameliorated pro-inflammatory pathways in vitro and in vivo which are thought to be highly relevant for acute and chronic GVHD pathogenesis. On May 24, 2019, the FDA approved ruxolitinib for steroid-refractory acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older. Ruxolitinib is currently being evaluated in clinical trial (REACH3: NCT03112603) for patients with steroid-refractory cGVHD. Disclosures Huarte: Incyte corporation: Employment, Equity Ownership. Parker:Incyte corporation: Employment, Equity Ownership. Juvekar:Incyte corporation: Employment, Equity Ownership. Oliver:Incyte corporation: Employment, Equity Ownership. Yao:Incyte corporation: Employment, Equity Ownership. Smith:Incyte corporation: Employment, Equity Ownership.