Gastrointestinal Acute Graft-versus-Host Disease in Children: Histology for Diagnosis, Mesenchymal Stromal Cells for Treatment, and Biomarkers for Prediction.

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Gastrointestinal Acute Graft-versus-Host Disease in Children: Histology for Diagnosis, Mesenchymal Stromal Cells for Treatment, and Biomarkers for Prediction of Response Friso G.J. Calkoen, Cornelia M. Jol-van der Zijde, M. Luisa Mearin, Joachim J. Schweizer, Anja M. Jansen-Hoogendijk, Helene Roelofs, Astrid G.S. van Halteren, R. Maarten Egeler, Maarten J.D. van Tol, Lynne M. Ball Biology of Blood and Marrow Transplantation Volume 19, Issue 11, Pages 1590-1599 (November 2013) DOI: 10.1016/j.bbmt.2013.08.006 Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Clinical response to MSC salvage therapy. Response to MSC treatment of children with steroid-refractory aGVHD of the GI tract was documented clinically on day 28 after first MSC infusion. Patients with CR have significantly better overall survival (A) and lower NRM (B). Log-rank Mantel-Cox tests were performed for statistical analysis. Biology of Blood and Marrow Transplantation 2013 19, 1590-1599DOI: (10.1016/j.bbmt.2013.08.006) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Flow diagram of patients with persistent symptoms. (A) The decision to infuse additional MSC was guided by the results obtained by endoscopy with biopsies in children with persistent or recurrent diarrhea. (B) Endoscopic evaluation of grade IV aGVHD before MSC infusion showing hemorrhage, denudation of the epithelium and ulceration. Histological examination was consistent with aGVHD. (C) Repeat endoscopy 22 days after MSC infusion showed evident healing of mucosa despite persistent diarrhea. Histological examination did not reveal active GVHD. Biology of Blood and Marrow Transplantation 2013 19, 1590-1599DOI: (10.1016/j.bbmt.2013.08.006) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 TNFR1 discriminate between patients with a CR and PR/NR on MSC treatment. At the start of systemic corticosteroids and 28 days after infusion of the first MSC serum TNFR1 concentrations (A), but not IL-2Rα (B) or REG3α (C), are significantly lower in patients with CR on day 28 compared with patients with PR or NR. ROC curves are shown at the different time points for TNFR1 (A). (D) Ratio of sCK18F versus CK18 after MSC discriminates between CR and PR/NR. P values for the different time-points using AUC (A) and Mann-Whitney tests (A-D) are depicted. Biology of Blood and Marrow Transplantation 2013 19, 1590-1599DOI: (10.1016/j.bbmt.2013.08.006) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Serum biomarkers at 28 days after the first MSC are predictive for survival. HGF (A), TNFR1 (B), IL-8 (C), and REG3α (D) concentrations in available samples at day + 28 after the first MSC infusion are increased in patients not alive at 1 year after transplantation. Using the median as a cutoff value, patients with low TNFR1 and low REG3α concentrations have a significantly better survival. The dotted horizontal line in the left panels represents the median of all values. Closed, half open and open symbols were used for CR, PR, and NR at day 28 after MSC infusion, respectively. Statistics were performed using Mann-Whitney (left panels) and log-rank (right panels) tests. Biology of Blood and Marrow Transplantation 2013 19, 1590-1599DOI: (10.1016/j.bbmt.2013.08.006) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Concentrations of serum biomarkers at time of GI biopsies. (A) Biomarker concentrations in serum are higher at the time of histological confirmed aGVHD compared with concentrations in sera taken at the time of negatively scored biopsies. A total of 45 time points at which combined biopsy and serum samples were available was evaluated independently whether this was before or after the first MSC infusion. (B) Sensitivity and specificity are shown by ROC curves if specificity was at least 80%. (C) Focusing on paired biopsy and serum samples obtained after MSC infusion, biomarker concentrations do not differ significantly between samples collected at the time of a positive or negative biopsy. Depicted P values were derived from Mann-Whitney (A and C) or AUC (B). Biology of Blood and Marrow Transplantation 2013 19, 1590-1599DOI: (10.1016/j.bbmt.2013.08.006) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions