Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation

Yoshihiro Inamoto; Paul J. Martin; Lynn E. Onstad; Guang Shing Cheng; Kirsten M. Williams; Iskra Pusic; Vincent T. Ho; Mukta Arora; Joseph Pidala; Mary E.D. Flowers; Ted A. Gooley; Richard L. Lawler; John A. Hansen; Stephanie J. Lee

doi:10.1016/j.jtct.2021.06.006

Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation

Yoshihiro Inamoto, Paul J. Martin, Lynn E. Onstad, Guang Shing Cheng, Kirsten M. Williams, Iskra Pusic, Vincent T. Ho, Mukta Arora, Joseph Pidala, Mary E.D. Flowers, Ted A. Gooley, Richard L. Lawler, John A. Hansen, Stephanie J. Lee

Medicine - Hematology, Oncology, Transplant

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

11 Scopus citations

Abstract

Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P =.04) or no chronic GVHD (P <.001). MMP-3 concentrations were higher in patients with BOS (P <.001) or non-BOS chronic GVHD (P <.001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P =.006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.

Original language	English (US)
Pages (from-to)	759.e1-759.e8
Journal	Transplantation and Cellular Therapy
Volume	27
Issue number	9
DOIs	https://doi.org/10.1016/j.jtct.2021.06.006
State	Published - Sep 1 2021

Bibliographical note

Funding Information:
We thank all members of the Chronic GVHD Consortium (U54 CA163438), which was funded as part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). The RDCRN is an initiative of the NCATS Office of Rare Disease Research, funded through collaboration between NCATS and the National Cancer Institute. Financial disclosure: This study was supported by grants from the National Cancer Institute (CA118953 and CA163438) and the Japan Society for the Promotion of Science (18K08345). Conflict of interest statement: Y.I. reports receiving personal fees from Novartis, Janssen, and Meiji Seika Pharma. P.J.M. reports receiving personal fees from Pfizer, the Pediatric Transplantation and Cellular Therapy Consortium, Genentech, Pharmacyclics, Neovii, Enlivex Therapeutics, Mesoblast, Rigel, Talaris, Janssen, and the Mount Sinai School of Medicine; nonfinancial support from Janssen, and others from AbGenomics (now AltruBio). S.J.L. reports receiving grants from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and serving on a steering committee for Incyte. The other authors have no conflicts of interest to report. Authorship statement: Y.I. P.J.M. J.A.H. and S.J.L. designed the study; Y.I. L.E.O. and T.A.G. performed the statistical analysis; G.S.C. K.M.W. I.P. V.T.H. M.A. J.P. and M.E.D.F. collected samples and data; R.L.L. performed experiments; and all authors wrote and critically revised the manuscript for important intellectual content and approved the manuscript for publication.

Funding Information:
Financial disclosure: This study was supported by grants from the National Cancer Institute ( CA118953 and CA163438 ) and the Japan Society for the Promotion of Science ( 18K08345 ).

Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy

Keywords

Allogeneic hematopoietic cell transplantation
Bronchiolitis obliterans
Chitinase-3-like-1 glycoprotein
Matrix metalloproteinase-3
Matrix metalloproteinase-9
Hematopoietic Stem Cell Transplantation/adverse effects
Lung Transplantation
Humans
Bronchiolitis Obliterans/etiology
Graft vs Host Disease
Matrix Metalloproteinase 9

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Multicenter Study
Journal Article
Research Support, N.I.H., Extramural

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10.1016/j.jtct.2021.06.006

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Inamoto, Y., Martin, P. J., Onstad, L. E., Cheng, G. S., Williams, K. M., Pusic, I., Ho, V. T., Arora, M., Pidala, J., Flowers, M. E. D., Gooley, T. A., Lawler, R. L., Hansen, J. A., & Lee, S. J. (2021). Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation. Transplantation and Cellular Therapy, 27(9), 759.e1-759.e8. https://doi.org/10.1016/j.jtct.2021.06.006

Inamoto, Y, Martin, PJ, Onstad, LE, Cheng, GS, Williams, KM, Pusic, I, Ho, VT, Arora, M, Pidala, J, Flowers, MED, Gooley, TA, Lawler, RL, Hansen, JA & Lee, SJ 2021, 'Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation', Transplantation and Cellular Therapy, vol. 27, no. 9, pp. 759.e1-759.e8. https://doi.org/10.1016/j.jtct.2021.06.006

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title = "Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation",

abstract = "Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P =.04) or no chronic GVHD (P <.001). MMP-3 concentrations were higher in patients with BOS (P <.001) or non-BOS chronic GVHD (P <.001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P =.006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.",

keywords = "Allogeneic hematopoietic cell transplantation, Bronchiolitis obliterans, Chitinase-3-like-1 glycoprotein, Matrix metalloproteinase-3, Matrix metalloproteinase-9, Hematopoietic Stem Cell Transplantation/adverse effects, Lung Transplantation, Humans, Bronchiolitis Obliterans/etiology, Graft vs Host Disease, Matrix Metalloproteinase 9",

author = "Yoshihiro Inamoto and Martin, {Paul J.} and Onstad, {Lynn E.} and Cheng, {Guang Shing} and Williams, {Kirsten M.} and Iskra Pusic and Ho, {Vincent T.} and Mukta Arora and Joseph Pidala and Flowers, {Mary E.D.} and Gooley, {Ted A.} and Lawler, {Richard L.} and Hansen, {John A.} and Lee, {Stephanie J.}",

note = "Funding Information: We thank all members of the Chronic GVHD Consortium (U54 CA163438), which was funded as part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). The RDCRN is an initiative of the NCATS Office of Rare Disease Research, funded through collaboration between NCATS and the National Cancer Institute. Financial disclosure: This study was supported by grants from the National Cancer Institute (CA118953 and CA163438) and the Japan Society for the Promotion of Science (18K08345). Conflict of interest statement: Y.I. reports receiving personal fees from Novartis, Janssen, and Meiji Seika Pharma. P.J.M. reports receiving personal fees from Pfizer, the Pediatric Transplantation and Cellular Therapy Consortium, Genentech, Pharmacyclics, Neovii, Enlivex Therapeutics, Mesoblast, Rigel, Talaris, Janssen, and the Mount Sinai School of Medicine; nonfinancial support from Janssen, and others from AbGenomics (now AltruBio). S.J.L. reports receiving grants from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and serving on a steering committee for Incyte. The other authors have no conflicts of interest to report. Authorship statement: Y.I. P.J.M. J.A.H. and S.J.L. designed the study; Y.I. L.E.O. and T.A.G. performed the statistical analysis; G.S.C. K.M.W. I.P. V.T.H. M.A. J.P. and M.E.D.F. collected samples and data; R.L.L. performed experiments; and all authors wrote and critically revised the manuscript for important intellectual content and approved the manuscript for publication. Funding Information: Financial disclosure: This study was supported by grants from the National Cancer Institute ( CA118953 and CA163438 ) and the Japan Society for the Promotion of Science ( 18K08345 ). Publisher Copyright: {\textcopyright} 2021 The American Society for Transplantation and Cellular Therapy",

year = "2021",

month = sep,

day = "1",

doi = "10.1016/j.jtct.2021.06.006",

language = "English (US)",

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T1 - Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation

AU - Inamoto, Yoshihiro

AU - Martin, Paul J.

AU - Onstad, Lynn E.

AU - Cheng, Guang Shing

AU - Williams, Kirsten M.

AU - Pusic, Iskra

AU - Ho, Vincent T.

AU - Arora, Mukta

AU - Pidala, Joseph

AU - Flowers, Mary E.D.

AU - Gooley, Ted A.

AU - Lawler, Richard L.

AU - Hansen, John A.

AU - Lee, Stephanie J.

N1 - Funding Information: We thank all members of the Chronic GVHD Consortium (U54 CA163438), which was funded as part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). The RDCRN is an initiative of the NCATS Office of Rare Disease Research, funded through collaboration between NCATS and the National Cancer Institute. Financial disclosure: This study was supported by grants from the National Cancer Institute (CA118953 and CA163438) and the Japan Society for the Promotion of Science (18K08345). Conflict of interest statement: Y.I. reports receiving personal fees from Novartis, Janssen, and Meiji Seika Pharma. P.J.M. reports receiving personal fees from Pfizer, the Pediatric Transplantation and Cellular Therapy Consortium, Genentech, Pharmacyclics, Neovii, Enlivex Therapeutics, Mesoblast, Rigel, Talaris, Janssen, and the Mount Sinai School of Medicine; nonfinancial support from Janssen, and others from AbGenomics (now AltruBio). S.J.L. reports receiving grants from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and serving on a steering committee for Incyte. The other authors have no conflicts of interest to report. Authorship statement: Y.I. P.J.M. J.A.H. and S.J.L. designed the study; Y.I. L.E.O. and T.A.G. performed the statistical analysis; G.S.C. K.M.W. I.P. V.T.H. M.A. J.P. and M.E.D.F. collected samples and data; R.L.L. performed experiments; and all authors wrote and critically revised the manuscript for important intellectual content and approved the manuscript for publication. Funding Information: Financial disclosure: This study was supported by grants from the National Cancer Institute ( CA118953 and CA163438 ) and the Japan Society for the Promotion of Science ( 18K08345 ). Publisher Copyright: © 2021 The American Society for Transplantation and Cellular Therapy

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P =.04) or no chronic GVHD (P <.001). MMP-3 concentrations were higher in patients with BOS (P <.001) or non-BOS chronic GVHD (P <.001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P =.006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.

AB - Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P =.04) or no chronic GVHD (P <.001). MMP-3 concentrations were higher in patients with BOS (P <.001) or non-BOS chronic GVHD (P <.001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P =.006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.

KW - Allogeneic hematopoietic cell transplantation

KW - Bronchiolitis obliterans

KW - Chitinase-3-like-1 glycoprotein

KW - Matrix metalloproteinase-3

KW - Matrix metalloproteinase-9

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Lung Transplantation

KW - Humans

KW - Bronchiolitis Obliterans/etiology

KW - Graft vs Host Disease

KW - Matrix Metalloproteinase 9

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SN - 2666-6367

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JO - Transplantation and Cellular Therapy

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ER -

Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation

Abstract

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Keywords

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