Treatment of chronic graft-versus-host disease with bortezomib

Chien Chun Steven Pai, Mingyi Chen, Annie Mirsoian, Steven K. Grossenbacher, Joseph Tellez, Erik Ames, Kai Sun, Jared Jagdeo, Bruce R. Blazar, William J. Murphy, Mehrdad Abedi

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center Bcells and lower B-cell activating factor gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft-versus-tumor (GVT) effects.Based on these animal studies, we initiated an intrapatient dose escalation clinical trial in patients with extensive steroid-intolerant, dependent, or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This trial was registered at www.clinicaltrials.gov as #NCT01672229.

Original languageEnglish (US)
Pages (from-to)1677-1688
Number of pages12
JournalBlood
Volume124
Issue number10
DOIs
StatePublished - Jan 1 2014

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Graft vs Host Disease
Grafts
Hematopoietic Stem Cell Transplantation
Stem cells
Therapeutics
B-Cell Activating Factor
Minor Histocompatibility Antigens
Transplants
Tumors
Skin
Proteasome Inhibitors
Germinal Center
Bearings (structural)
Bortezomib
Lymphoma
Neoplasms
B-Lymphocytes
Steroids
Maintenance
Gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Pai, C. C. S., Chen, M., Mirsoian, A., Grossenbacher, S. K., Tellez, J., Ames, E., ... Abedi, M. (2014). Treatment of chronic graft-versus-host disease with bortezomib. Blood, 124(10), 1677-1688. https://doi.org/10.1182/blood-2014-02-554279

Treatment of chronic graft-versus-host disease with bortezomib. / Pai, Chien Chun Steven; Chen, Mingyi; Mirsoian, Annie; Grossenbacher, Steven K.; Tellez, Joseph; Ames, Erik; Sun, Kai; Jagdeo, Jared; Blazar, Bruce R.; Murphy, William J.; Abedi, Mehrdad.

In: Blood, Vol. 124, No. 10, 01.01.2014, p. 1677-1688.

Research output: Contribution to journalArticle

Pai, CCS, Chen, M, Mirsoian, A, Grossenbacher, SK, Tellez, J, Ames, E, Sun, K, Jagdeo, J, Blazar, BR, Murphy, WJ & Abedi, M 2014, 'Treatment of chronic graft-versus-host disease with bortezomib', Blood, vol. 124, no. 10, pp. 1677-1688. https://doi.org/10.1182/blood-2014-02-554279
Pai CCS, Chen M, Mirsoian A, Grossenbacher SK, Tellez J, Ames E et al. Treatment of chronic graft-versus-host disease with bortezomib. Blood. 2014 Jan 1;124(10):1677-1688. https://doi.org/10.1182/blood-2014-02-554279
Pai, Chien Chun Steven ; Chen, Mingyi ; Mirsoian, Annie ; Grossenbacher, Steven K. ; Tellez, Joseph ; Ames, Erik ; Sun, Kai ; Jagdeo, Jared ; Blazar, Bruce R. ; Murphy, William J. ; Abedi, Mehrdad. / Treatment of chronic graft-versus-host disease with bortezomib. In: Blood. 2014 ; Vol. 124, No. 10. pp. 1677-1688.
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