Introduction For numerous malignant and non-malignant hematological diseases allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy. However, a major complication is the acute graft versus host disease (aGVHD), which is life-threatening and substantially reduces efficacy of HSCT. In particular, the outcome for patients with severe steroid-resistant aGVHD is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of aGVHD.
Objective Feasibility of the generation mesenchymal stroma cells (MSCs) expanded with human plasma and platelet lysate (hPPL) was tested as well as the feasibility and safety of the application of MSCs in patients with steroid-refractory extensive aGVHD.
Method In an open-label, non-randomized prospective phase I/II study MSCs were extracted from the bone marrow of healthy volunteers, expanded with human plasma and platelet lysate (hPPL), and stored. Patients with steroid-refractory extensive aGVHD were treated with ∼2×106/kg MSC. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells.
Results Between January 2009 and December 2010, 18 patients were treated, 5 children and 13 adults, median age was 32.5 years (range 1.3–65.9). Organ involvement of the aGVHD was 67% skin, 83% gastro-intestinal and 28% liver. Overall grade was II for 4 (22%), III for 13 (72%), and IV for 1(6%) patients. 1 patient received one infusion, all other patients received two or more infusions. No patient had side-effects during or immediately after infusions of the MSC. Median follow-up was 5.5 months (range 0.33–12). Complete overall response was observed in 11 (61%) patients after a median of 65 days (range 10–184 days). The overall survival was significant better (p <0.001) compared to non-responders. Of the 11 patients who reached a CR, 8 relapsed median 59 days (1–244) after reaching CR. Three children with subsequently limited cGVHD, allo immune lung and auto-immune cytopenia and 5 adults with all relapse GVHD of the gut, median 98 days (35–302 days). However, GVHD of the gut was then sensitive for the treatment with steroids. Overall, 7 patients died, 4 due to progression of aGVHD, 1 patient due to abdominal bleeding and 2 due to sepsis.
Conclusion Generation and infusion of MSCs in steroid-resistant aGVHD grade II- IV is a feasible, safe and very effective. In addition, also patients who initially responded to MSCs but develop later a relapse of aGVHD during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.