Janus Kinase (JAK) 1 Inhibition Results in Significant Changes in Serum Proteins and Peripheral T-Cell Populations That Correlated with Clinical Scores in Chronic Graft Versus Host Disease (GVHD) Patients (an Analysis from GRAVITAS-309)

Background: Chronic GVHD (cGVHD) occurs in 30-70% of allogeneic hematopoietic cell transplantation patients, and the rate has increased over the past 2 decades. Based on the degree of organ involvement, cGVHD is classified as mild, moderate, or severe. Standard treatment includes systemic corticosteroids (CS), together with immunosuppressive agents. GRAVITAS-309 (NCT03584516) was designed as a 2-part, multicenter, randomized trial to assess efficacy and safety of itacitinib, an orally bioavailable, selective JAK1 inhibitor, in combination with CS as first-line treatment for moderate to severe cGVHD. The dose-finding, open-label, randomized portion of the study initially investigated itacitinib at 200 mg once daily (qd) and 300 mg qd in combination with CS (methylprednisolone or prednisone); both doses were well tolerated. The trial was expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300 mg qd cohort was expanded and a CS monotherapy cohort was added. Results from the expanded portion of the study (n=139 patients) showed improved overall response rate (ORR) at 6 months in patients treated with itacitinib + CS vs CS alone (Im, et al. Blood 2022;140[Suppl 1]:1870). Here, we analyzed samples collected from patients in 4 cohorts (cohort A [300 mg qd], cohort B [400 mg qd], cohort C [300 mg bid], and cohort D [CS alone]) for systemic proteins and immune cell populations, to support investigation into the itacitinib mechanism of action and to correlate with clinical outcomes. Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected before treatment (baseline, day 1), and day 7, day 14 (PBMCs only), and day 28 following treatment initiation. Serum proteins were analyzed using the OLINK Target 96 platform, and circulating T-cell subsets were measured using flow cytometry of PBMCs and presented as a percentage of parent population. Samples were assessed irrespective of patients' response. Most of the patients (70-100% per cohort) with samples available for analysis were responders (achieved complete or partial responses). Results: Serum levels of proteins, including several proposed as potential prognostic cGVHD biomarkers, changed significantly at day 28 relative to baseline following treatment with itacitinib (Table 1). Levels of elafin, a marker of acute GVHD of the skin, were significantly reduced and levels of dickkopf-3 (DKK3), a marker of sclerotic and nonsclerotic cGVHD, were significantly increased in itac