ArticlesMesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study
Introduction
Allogeneic haemopoietic-stem-cell transplantation is the treatment of choice for many malignant and non-malignant disorders.1, 2 Severe graft-versus-host disease (GVHD) is a life-threatening complication after this treatment and donor lymphocyte infusion is used for treatment or prevention of relapse of leukaemia.3, 4 Steroids are still the first-line treatment for established GVHD with a response rate of 30–50%; however, the outcome for patients with severe, steroid-resistant, acute GVHD is poor, and overall survival is low.1, 3, 4, 5
Mesenchymal stem cells are multipotent bone-marrow cells able to differentiate in vitro and in vivo into tissues of mesenchymal origin.6, 7 Moreover, these cells provide support for the growth and differentiation of haemopoietic progenitor cells in bone-marrow microenvironments and, in animal models, promote engraftment of haemopoietic cells.8 In co-culture experiments with allogeneic lymphocytes, mesenchymal stem cells do not induce lymphocyte proliferation, interferon-γ production, or upregulation of activation markers.9, 10
Mesenchymal stem cells suppress proliferation of activated lymphocytes in vitro in a dose-dependent, non-HLA-restricted, manner.9, 10, 11 In a baboon skin-graft model, Bartholomew and co-workers11 showed that infusion of ex-vivo expanded donor-derived or third-party cells prolonged the time to rejection of histoincompatible skin grafts. Furthermore, infused cells improve the outcome of acute renal, neural, and lung injury, possibly by promoting a shift from production of proinflammatory cytokines to anti-inflammatory cytokines at the site of injury.12, 13, 14
In phase I and II trials, HLA-identical mesenchymal stem cells expanded ex vivo have been infused to promote haemopoietic recovery after autologous and allogeneic haemopoietic-stem-cell transplantation and to treat patients with osteogenesis imperfecta.15, 16, 17, 18, 19, 20 So far, neither acute nor long-term adverse events have been reported after infusion of mesenchymal stem cells. Two reports on the use of in-vitro expanded cells for the treatment of severe, acute GVHD have recently been published.21, 22
To facilitate large-scale, multicentre trials, the European Group for Blood and Marrow Transplantation Developmental Committee has adopted a common protocol for expansion of mesenchymal stem cells. We report the results of a multicentre, phase II study of the use of these cells in 55 patients with severe and steroid-resistant, acute GVHD.
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Patients
Between October, 2001, and January, 2007, patients of all ages with grade 2–4 GVHD after haemopoietic-stem-cell transplantation, who did not respond to steroid treatment (≥2 mg per kg per day) for at least 7 days, or with progression of at least one grade within 72 h were eligible for the study. 55 patients were treated (table 1); 48 had developed GVHD after transplantation of haemopoietic stem cells and seven after donor lymphocyte infusion. Most patients had grade 3 or 4 GVHD involving two or
Results
92 infusions of mesenchymal stem cells were given; 27 patients had one infusion, while 28 had two or more (figure 1, table 3). Of the 28 patients treated with multiple infusions, 15 received cells derived from two or more donors. No patients had acute side-effects either during or after infusion; and none have had late side-effects so far. Median time from transplantation of haemopoietic stem cells to infusion of mesenchymal stem cells was 103 days (min–max range 27–533).
Just over half the
Discussion
39 of 55 patients with steroid-resistant, severe, acute GVHD responded to treatment with mesenchymal stem cells. Survival in those with complete response was significantly higher and transplantation-related mortality after infusion was significantly lower than in people with partial or no response. The clinical course of the 13 patients with progressive disease despite treatment may represent the natural progression of severe GVHD resulting in death in most patients. No major toxicities were
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These authors contributed equally