Heterogeneity of chronic graft-versus-host disease biomarkers: Association with CXCL10 and CXCR3+ NK cells

Amina Kariminia; Shernan G. Holtan; Sabine Ivison; Jacob Rozmus; Marie Josée Hebert; Paul J. Martin; Stephanie J. Lee; Daniel Wolff; Peter Subrt; Sayeh Abdossamadi; Susanna Sung; Jan Storek; Megan Levings; Mahmoud Aljurf; Mukta Arora; Corey Cutler; Geneviève Gallagher; John Kuruvilla; Jeff Lipton; Thomas J. Nevill; Laura F. Newell; Tony Panzarella; Joseph Pidala; Gizelle Popradi; David Szwajcer; Jason Tay; Cynthia L. Toze; Irwin Walker; Stephen Couban; Barry E. Storer; Kirk R. Schultz

doi:10.1182/blood-2015-09-668251

Heterogeneity of chronic graft-versus-host disease biomarkers: Association with CXCL10 and CXCR3⁺ NK cells

Amina Kariminia, Shernan G. Holtan, Sabine Ivison, Jacob Rozmus, Marie Josée Hebert, Paul J. Martin, Stephanie J. Lee, Daniel Wolff, Peter Subrt, Sayeh Abdossamadi, Susanna Sung, Jan Storek, Megan Levings, Mahmoud Aljurf, Mukta Arora, Corey Cutler, Geneviève Gallagher, John Kuruvilla, Jeff Lipton, Thomas J. NevillLaura F. Newell, Tony Panzarella, Joseph Pidala, Gizelle Popradi, David Szwajcer, Jason Tay, Cynthia L. Toze, Irwin Walker, Stephen Couban, Barry E. Storer, Kirk R. Schultz

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3⁺ CD56^bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.

Original language	English (US)
Pages (from-to)	3082-3091
Number of pages	10
Journal	Blood
Volume	127
Issue number	24
DOIs	https://doi.org/10.1182/blood-2015-09-668251
State	Published - Jun 16 2016

Bibliographical note

Funding Information:
The authors thank centers that contributed to the Chronic GVHD Consortium, including Vanderbilt (Madan Jagasia), Roswell Park (George Chen), Stanford University (Sally Arai), Cleveland Clinic Taussig Cancer Institute (Betty Hamilton), Washington University (Iskra Pusic), and Cornell University (Sebastian Ma). This work was supported by a Canadian Institutes of Health Operating Grant; by the CIHR/Wyeth Clinical Research Chair in Transplantation (K.R.S.); by the Canadian National Transplant Research Program (funded by the CIHR); by the Office of Research in Women's Health and the National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award No. 2K12HD043488 (S.G.H.); by the Medical Foundation of Oregon (S.G.H.); and by the Deutsche José Carreras Leukämie-Stiftung (D.W.). The Chronic GVHD Consortium is funded via collaboration between the Center for Advancing Translational Sciences and the National Cancer Institute (NCI) (U54CA163438). Support for the discovery samples was provided by grant CA118953 from NCI. The Canadian Bone Marrow Transplant Group Clinical Trials Network provided samples from CBMTG 0601 (funded by National Institutes of Health/NCI 1R01CA108752-01A2) and samples from CBMTG 0801 (funded by CIHR).

Publisher Copyright:
© 2016 by The American Society of Hematology.

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10.1182/blood-2015-09-668251

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Kariminia, A., Holtan, S. G., Ivison, S., Rozmus, J., Hebert, M. J., Martin, P. J., Lee, S. J., Wolff, D., Subrt, P., Abdossamadi, S., Sung, S., Storek, J., Levings, M., Aljurf, M., Arora, M., Cutler, C., Gallagher, G., Kuruvilla, J., Lipton, J., ... Schultz, K. R. (2016). Heterogeneity of chronic graft-versus-host disease biomarkers: Association with CXCL10 and CXCR3⁺ NK cells. Blood, 127(24), 3082-3091. https://doi.org/10.1182/blood-2015-09-668251

Kariminia, A, Holtan, SG, Ivison, S, Rozmus, J, Hebert, MJ, Martin, PJ, Lee, SJ, Wolff, D, Subrt, P, Abdossamadi, S, Sung, S, Storek, J, Levings, M, Aljurf, M, Arora, M, Cutler, C, Gallagher, G, Kuruvilla, J, Lipton, J, Nevill, TJ, Newell, LF, Panzarella, T, Pidala, J, Popradi, G, Szwajcer, D, Tay, J, Toze, CL, Walker, I, Couban, S, Storer, BE & Schultz, KR 2016, 'Heterogeneity of chronic graft-versus-host disease biomarkers: Association with CXCL10 and CXCR3⁺ NK cells', Blood, vol. 127, no. 24, pp. 3082-3091. https://doi.org/10.1182/blood-2015-09-668251

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title = "Heterogeneity of chronic graft-versus-host disease biomarkers: Association with CXCL10 and CXCR3+ NK cells",

abstract = "Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+ CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.",

author = "Amina Kariminia and Holtan, {Shernan G.} and Sabine Ivison and Jacob Rozmus and Hebert, {Marie Jos{\'e}e} and Martin, {Paul J.} and Lee, {Stephanie J.} and Daniel Wolff and Peter Subrt and Sayeh Abdossamadi and Susanna Sung and Jan Storek and Megan Levings and Mahmoud Aljurf and Mukta Arora and Corey Cutler and Genevi{\`e}ve Gallagher and John Kuruvilla and Jeff Lipton and Nevill, {Thomas J.} and Newell, {Laura F.} and Tony Panzarella and Joseph Pidala and Gizelle Popradi and David Szwajcer and Jason Tay and Toze, {Cynthia L.} and Irwin Walker and Stephen Couban and Storer, {Barry E.} and Schultz, {Kirk R.}",

note = "Funding Information: The authors thank centers that contributed to the Chronic GVHD Consortium, including Vanderbilt (Madan Jagasia), Roswell Park (George Chen), Stanford University (Sally Arai), Cleveland Clinic Taussig Cancer Institute (Betty Hamilton), Washington University (Iskra Pusic), and Cornell University (Sebastian Ma). This work was supported by a Canadian Institutes of Health Operating Grant; by the CIHR/Wyeth Clinical Research Chair in Transplantation (K.R.S.); by the Canadian National Transplant Research Program (funded by the CIHR); by the Office of Research in Women's Health and the National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award No. 2K12HD043488 (S.G.H.); by the Medical Foundation of Oregon (S.G.H.); and by the Deutsche Jos{\'e} Carreras Leuk{\"a}mie-Stiftung (D.W.). The Chronic GVHD Consortium is funded via collaboration between the Center for Advancing Translational Sciences and the National Cancer Institute (NCI) (U54CA163438). Support for the discovery samples was provided by grant CA118953 from NCI. The Canadian Bone Marrow Transplant Group Clinical Trials Network provided samples from CBMTG 0601 (funded by National Institutes of Health/NCI 1R01CA108752-01A2) and samples from CBMTG 0801 (funded by CIHR). Publisher Copyright: {\textcopyright} 2016 by The American Society of Hematology.",

year = "2016",

month = jun,

day = "16",

doi = "10.1182/blood-2015-09-668251",

language = "English (US)",

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pages = "3082--3091",

journal = "Blood",

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publisher = "American Society of Hematology",

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TY - JOUR

T1 - Heterogeneity of chronic graft-versus-host disease biomarkers

T2 - Association with CXCL10 and CXCR3+ NK cells

AU - Kariminia, Amina

AU - Holtan, Shernan G.

AU - Ivison, Sabine

AU - Rozmus, Jacob

AU - Hebert, Marie Josée

AU - Martin, Paul J.

AU - Lee, Stephanie J.

AU - Wolff, Daniel

AU - Subrt, Peter

AU - Abdossamadi, Sayeh

AU - Sung, Susanna

AU - Storek, Jan

AU - Levings, Megan

AU - Aljurf, Mahmoud

AU - Arora, Mukta

AU - Cutler, Corey

AU - Gallagher, Geneviève

AU - Kuruvilla, John

AU - Lipton, Jeff

AU - Nevill, Thomas J.

AU - Newell, Laura F.

AU - Panzarella, Tony

AU - Pidala, Joseph

AU - Popradi, Gizelle

AU - Szwajcer, David

AU - Tay, Jason

AU - Toze, Cynthia L.

AU - Walker, Irwin

AU - Couban, Stephen

AU - Storer, Barry E.

AU - Schultz, Kirk R.

N1 - Funding Information: The authors thank centers that contributed to the Chronic GVHD Consortium, including Vanderbilt (Madan Jagasia), Roswell Park (George Chen), Stanford University (Sally Arai), Cleveland Clinic Taussig Cancer Institute (Betty Hamilton), Washington University (Iskra Pusic), and Cornell University (Sebastian Ma). This work was supported by a Canadian Institutes of Health Operating Grant; by the CIHR/Wyeth Clinical Research Chair in Transplantation (K.R.S.); by the Canadian National Transplant Research Program (funded by the CIHR); by the Office of Research in Women's Health and the National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award No. 2K12HD043488 (S.G.H.); by the Medical Foundation of Oregon (S.G.H.); and by the Deutsche José Carreras Leukämie-Stiftung (D.W.). The Chronic GVHD Consortium is funded via collaboration between the Center for Advancing Translational Sciences and the National Cancer Institute (NCI) (U54CA163438). Support for the discovery samples was provided by grant CA118953 from NCI. The Canadian Bone Marrow Transplant Group Clinical Trials Network provided samples from CBMTG 0601 (funded by National Institutes of Health/NCI 1R01CA108752-01A2) and samples from CBMTG 0801 (funded by CIHR). Publisher Copyright: © 2016 by The American Society of Hematology.

PY - 2016/6/16

Y1 - 2016/6/16

N2 - Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+ CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.

AB - Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+ CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.

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