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2197 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)

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster I
Hematology Disease Topics & Pathways:
Research, adult, Translational Research, Combination therapy, GVHD, Diseases, Immune Disorders, Therapies, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Michael Pratta1*, Angelina Volkova1*, Maureen Bleam1*, Rodica Morariu-Zamfir1*, Beth Rumberger1*, Stephen Douglass1*, Susan H. Smith1*, Valkal Bhatt1*, John Galvin1, Annie Im2, Sophie Paczesny3, Kirk R. Schultz4 and Steven Z. Pavletic5

1Incyte Corporation, Wilmington, DE
2University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA
3Medical University of South Carolina, Charleston, SC
4University of British Columbia, Vancouver, BC, Canada
5National Cancer Institute-NIH, Bethesda, MD

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 itacitinib cohorts only. Based on a repeated measures correlation analysis, both markers significantly correlated with overall clinical skin scores (elafin: r=+0.43; DKK3: r=-0.53; both P<0.001). Serum levels of other reported markers of cGVHD, including osteopontin, C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, were significantly decreased exclusively in itacitinib-treated cohorts, and not in the CS only cohort. Some proteins, including matrix metalloproteinase (MMP) 3, increased in all cohorts, suggesting that changes in these proteins cannot be attributed to itacitinib alone, but may reflect response to CS; other proteins, such as suppression of tumorigenicity (ST2), remained unchanged in response to treatment in all cohorts. CS treatment alone resulted in an increase in naive CD4 T cells (CD4+CD8>CD45RA+CCR7) and a corresponding reduction of CD4 effector memory T cells (CD4+CD8>CD45RACCR7+) within 28 days (Figure 1, cohort D). Changes in naive CD4 T cells following CS monotherapy were significantly attenuated by itacitinib (P<0.05 vs CS at day 28), particularly at the 400 mg qd dose (Figure 1, cohort B), which demonstrated the best ORR at 6 months (53% with 400 mg qd vs 36% with CS).

Conclusions: Analysis of patient samples from GRAVITAS-309 revealed that serum elafin and DKK3 levels significantly correlated with skin GVHD scores, possibly reflecting the systemic origin of observed skin manifestations. Serum levels of osteopontin, CXCL9, and CXCL10 were specifically reduced by itacitinib in patients with cGVHD and may represent potential pharmacodynamic markers. Observed changes in different peripheral T-cell populations in patients’ samples following itacitinib treatment were consistent with those reported in murine GVHD models, suggesting a potential role of naive CD4+ T cells in driving this disease. Planned future analyses will include identification of novel biomarkers that correlate with organ involvement.


Disclosures: Pratta: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Volkova: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Bleam: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Morariu-Zamfir: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rumberger: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Douglass: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Smith: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Bhatt: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Galvin: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Im: Incyte Corporation: Research Funding; Abbvie, CTI BioPharma, Sanofi: Consultancy; DuoOncology: Current equity holder in publicly-traded company. Paczesny: Indiana University Research and Technology Corporation: Patents & Royalties: Biomarkers and assays to detect chronic graft versus host disease (U.S. Patent 10,571,478 B2).

*signifies non-member of ASH