Advances in the clinical management of GVHD.
The principal cause of mortality and morbidity following hematopoietic cell transplantation (HCT) is graft-versus-host disease (GVHD). Studies in murine models have revealed that inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) promote destruction of host tissue following HCT. Elevated plasma levels of soluble TNF receptor 1 have been associated with patients with GVHD and blocking TNF-alpha in experimental models has shown a reduced incidence of GVHD. Based on this finding, patients with new onset GVHD were treated with steroids plus the TNF-alpha inhibitor, etanercept, on a previously reported pilot trial (n=20) and a phase 2 trial (n=41) and their outcomes were compared with those of contemporaneous patients with GVHD (n=99) whose initial therapy was steroids alone. Patients treated with etanercept were more likely to achieve CR than were patients treated with steroids alone. Plasma TNFR1 levels, a biomarker for GVHD activity, were elevated at GVHD onset and decreased significantly only in patients with CR. A four protein fingerprint of IL-2Ralpha, TNFR1, IL-8, and HGF in the plasma has been identified to predict whether a patient will be at high-risk for GVHD based on biomarker analysis. In univariate and multivariate analysis, this four-protein fingerprint has shown a strong association with the grade of acute GVHD, and it can stratify patients into low- and high-risk groups and can be used as a laboratory-based screening method, to diagnose and perhaps treat patients preemptively.
Ferrara
James L M
JL
Blood & Marrow Transplant Program, The University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive, SPC 5942, Room 6308, Ann Arbor, MI48109-5942, USA. ferrara@umich.edu
D000818:Animals; D015415:Biomarkers; D019468:Disease Management; D000068800:Etanercept; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D017228:Hepatocyte Growth Factor; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D016209:Interleukin-8; D015375:Receptors, Interleukin-2; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I; D013256:Steroids / Q000627:therapeutic use
D015415:Biomarkers; D007074:Immunoglobulin G; D016209:Interleukin-8; D015375:Receptors, Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D013256:Steroids; D017228:Hepatocyte Growth Factor; D000068800:Etanercept