TY - JOUR
T1 - A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease
AU - Pratta, Michael
AU - Paczesny, Sophie
AU - Socie, Gerard
AU - Barkey, Natalie
AU - Liu, Hao
AU - Owens, Sherry
AU - Arbushites, Michael C.
AU - Schroeder, Mark A.
AU - Howell, Michael D.
N1 - Funding Information:
This study was funded by Incyte Corporation (Wilmington, DE, USA). The authors thank Mary Jo Penna for manuscript review. Copyedit and submission assistance was provided by ICON (Blue Bell, PA, USA), which was funded by Incyte Corporation. Michael Pratta designed and performed research, analysed and interpreted data, and wrote the manuscript; Sophie Paczesny, Gerard Socie, and Mark A. Schroeder reviewed and interpreted data; Natalie Barkey wrote the manuscript; Hao Liu and Sherry Owens reviewed data and performed statistical analysis; Michael C. Arbushites provided clinical information on participant samples; Michael D. Howell designed research, interpreted data, and reviewed the manuscript.
Publisher Copyright:
© 2022 INCYTE Corporation. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
PY - 2022/8
Y1 - 2022/8
N2 - A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).
AB - A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).
KW - JAK inhibitors
KW - acute graft-versus-host disease
KW - biomarkers
KW - itacitinib
UR - http://www.scopus.com/inward/record.url?scp=85131511213&partnerID=8YFLogxK
U2 - 10.1111/bjh.18300
DO - 10.1111/bjh.18300
M3 - Article
C2 - 35689489
AN - SCOPUS:85131511213
SN - 0007-1048
VL - 198
SP - 729
EP - 739
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 4
ER -