Treatment of severe acute graft-versus-host disease with mesenchymal stromal cells: a comparison with non-MSC treated patients

Abstract

During the last years, considerable hope has been attributed to mesenchymal stromal cells (MSC) as treatment for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). There have been a number of mainly small studies evaluating the effect of MSC treatment of severe aGVHD [1–5]. We compared all adult patients who were given MSC between 2002 and 2006 as treatment for steroid-resistant grade III–IV aGVHD with all consecutive adult patients with severe steroid-resistant aGVHD not treated with MSC during the same time period. Patient and donor characteristics are displayed in Supplementary Table 1. MSC were used according to steroid refractoriness of aGVHD and to cell availability. All patients included in the study gave informed consent. Details and method of MSC generation and evaluation of response have been published previously [3, 6]. We evaluated survival as primary endpoint, since this is most important and definite. Infections were secondary endpoints. Acute GVHD was diagnosed on the basis of clinical symptoms and/or biopsies (skin, liver, gastrointestinal tract, or oral mucosa) according to standard criteria. There were no significant differences in organ involvement or severity of aGVHD between the two groups (Supplementary Table 1). Acute GVHD grade III occurred a median of 63 (21–115) and 56 (21–112) days after HSCT in the MSC and control group, respectively (p = 0.96). In the MSC-treated patients, additional treatment (besides steroids) consisted of daclizumab (n = 3), infliximab (n = 4), sirolimus (n = 3), rituximab (n = 2) and mycophenolate mofetil (MMF, n = 1). Among the controls, additional treatment consisted of daclizumab (n = 3), infliximab (n = 3), sirolimus (n = 3), MMF (n = 4), anti-thymocyte globulin (ATG, n = 2), psoralen and UV A light (PUVA, n = 3) and extracorporeal photopheresis (ECP, n = 4). MSC were given to patients with a median of 8 (0–37) days after diagnosis of aGVHD grade III. A total of 22 doses of MSC were given. Median MSC dose was 1.4 9 10/kg patient (0.65–2.0). Among patients given MSCs, complete response (CR) occurred in 6 patients, partial response (PR) in one, stable disease (SD) in one and progressive disease (PD) in seven patients. Overall survival was 53 % (95 % CI 27–79 %) versus 38 % (12–64 %) at 100 days and 20 % (2–38 %) versus 15 % (0–35 %) 1 year after development of GVHD in the MSC group and controls, respectively (Fig. 1a) (p = 0.42). Non-relapse mortality (NRM) was 40 % (15–65 %) versus 54 % (27–81 %) at 100 days and 73 % (52–94 %) versus 77 % (56–98 %) 1 year after GVHD in the two groups, respectively (Fig. 1b) (p = 0.63). Median survival time was 105 days (18–1856) and 49 days (6–2107) for MSC patients and controls, p = 0.21. There was no correlation between the number of MSC doses and survival. We found no difference in survival between early and late disease and older patients ([50 years) tended (p = 0.09) to have better survival. There were no statistical differences in the incidences of infections like bacteraemia, cytomegalovirus (CMV) reactivation and disease and post-transplant Electronic supplementary material The online version of this article (doi:10.1007/s12185-012-1218-3) contains supplementary material, which is available to authorized users.