Abstract
We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II–IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485–5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144–4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389–0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.
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Acknowledgements
We thank the research technicians S Heijhuurs, S Hol and Z Stachova for processing patient materials and also thank the multiplex immunoassay core facility at the UMC Utrecht for their cooperation. This work was partly supported by a grant from the Dutch Cancer Society to LEvdW (UU 2011-5250).
Author Contributions
LCJtB, CM, LEvdW, JK, JJB and CAL designed, interpreted and analyzed the data. CM, LEvdW and MP performed experiments. CM, LEvdW, LCJtB and JK wrote the manuscript. NMW, ICMS-C, JK, LCJtB and JJB designed the study. EJP, ES, KAT, KW, MB, AECB, MLHC, GI, JJJ, CH, SZ, GH, MP and NMW provided suggestions on the experiments and commented on the manuscript.
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te Boome, L., Mansilla, C., van der Wagen, L. et al. Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells. Leukemia 29, 1839–1846 (2015). https://doi.org/10.1038/leu.2015.89
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DOI: https://doi.org/10.1038/leu.2015.89
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