Predicting Complete Response to Itacitinib and Corticosteroids in Acute Graft Versus Host Disease

Background Acute graft versus host disease (aGVHD) represents a serious and potentially life threatening condition in patients receiving hematopoietic stem cell transplantation (HSCT). aGVHD is characterized by increased levels of inflammatory mediators and activated T cells in circulation leading to tissue and organ damage. In a parallel-cohort phase 1 trial (NCT02614612) that evaluated the combination of corticosteroids and itacitinib, a potent and highly selective JAK1 inhibitor, we utilized broad proteomic analysis to identify potentially predictive biomarkers of therapeutic response to the combination treatment. Methods Plasma was collected from 25 patients enrolled in the clinical trial prior to and at designated times following treatment. Proteomic analysis on plasma was conducted by OLINK Proteomics using a proximity extension assay. Statistical differences were identified using unpaired T tests and one-way ANOVA. Significance was conferred when p Results Patients were stratified based on their overall response to treatment with itacitinib and corticosteroid at day 28 (based on CIBMTR). Patients included 10 complete responders (CR), 1 very good partial responder (VGPR), 8 partial responders (PR) and 6 patients with progressive disease and/or death (PD/death) prior to day 28. Biomarkers were identified and associated with therapeutic response by comparing the levels of approximately 1000 proteins in the CR (N=10) and PD/Death (N=6) cohorts specifically. Initial analysis identified 55 proteins significantly upregulated (P Novel biomarkers identified include macrophage chemotactic protein 3 (MCP3/CCL7), stem cell factor (SCF/KIT-L), interleukin 8 (IL8), paraoxonase 3 (PON3), calcitonin (CALCA), and tumor necrosis factor receptor super family 6B (TNFRSF6B). (Table 1). Each of these biomarkers demonstrated a significant (P Conclusion Biomarkers identified in this study may be useful in predicting complete responses to treatment with a combination of corticosteroids and itacitinib in patients with aGVHD post HSCT.