Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study

doi:10.1016/S0140-6736(08)60690-X

The Lancet

Volume 371, Issue 9624, 10–16 May 2008, Pages 1579-1586

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https://doi.org/10.1016/S0140-6736(08)60690-X Get rights and content

Summary

Background

Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation.

Methods

Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells.

Findings

Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1·4×10⁶ (min–max range 0·4–9×10⁶) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p=0·002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p=0·018).

Interpretation

Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.

Funding

Swedish Cancer Society, Children's Cancer Foundation, Swedish Research Council, Cancer Society in Stockholm, Cancer and Allergy Foundation, Karolinska Institutet, Istituto Superiore di Sanità, European Union, Regione Lombardia, Fondazione CARIPLO, Associazione Italiana Ricerca contro il Cancro, Compagnia di San Paolo Torino, Progetto CARIGE Cellule Staminali, European Commission, Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Ricerca Finalizzata Regione Liguria 2005 Assistenza Domiciliare, Dutch Programme for Tissue Engineering.

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.

Section snippets

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

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ArticlesMesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Blood

Bone

Exp Hematol

Exp Hematol

Blood

Biol Blood Marrow Transplant

Blood

Lancet

Cytotherapy

Blood

Biol Blood Marrow Transplant

Blood

Graft-versus-host disease in dog and man: the Seattle experience

Immunol Rev

Articles
Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study