Treatment of steroid resistant grade II to IV acute GVHD by infusion of mesenchymal stromal cells expanded with platelet lysate - a phase I/II study

      Despite major improvements in the last decade in the field of HSCT, steroid-resistent acute graft versus host disease (aGVHD) remains a life-threatening complication. In an open-label, non-randomized prospective phase I/II study 50 patients with steroid-refractory GVHD grade II-IV were treated with MSC. Response rates, TRM and other adverse events were assessed for up to 12 months. Immunological changes after infusion of MSC were characterized in vitro. Anti-viral and antileukemia responses of reactive T-cells were tested and phenotypical changes in immune cells were followed up as were cytokines implicated in GVHD. MSC production takes ±22 days to expand from bone marrow to P3, resulting in ± 59x10e6 MSC per 2-layer CellStack. Between January 2009 and July 2012, 48 out of 50 patients included were eligible for analysis (7 children,41 adults). Mean age was 44.9 years (1.3-68.9). Organs involved were skin (52%), GI tract (88%) and liver (35%). Overall GVHD grade was II for 12 (25%), III for 33 (69%), and IV for 3 (6%) patients. Mean number of infusions were 3 (1–4). No severe side effects were observed upon infusions. Median follow up was 5,0 months (0.3-46.5). Complete overall response of aGVHD was observed in 24 patients (50%) after a median of 53 days (3–116 days). Overall survival was significantly improved in responders when compared to non-responders (p <0.001). Patients who relapsed with GVHD of the gut were again sensitive to steroids, or a second cycle of MSC (one patient). Immunological monitoring shows that anti-viral and anti-leukemia reactive T-cells are well preserved in all patients who responded to MSC treatment. In addition we identified a combination of biomarkers that 2 weeks after initiation of treatment predicts a complete resolution of GVHD, whilst this usually becomes clinically apparent after months. Identified biomarkers predict early an usually late clinical resolution of GVHD and thus might be useful to early guide clinical decision making.
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