Mesenchymal Stem Cells As a Treatment for Steroid-Resistant Acute Graft Versus Host Disease (aGVHD); A Multicenter Phase I/II Study

Allogeneic hematopoietic stem cell (HSC) transplantation is an effective therapy for a number of diseases. However, severe graft versus host disease (GVHD) remains a life-threatening complication after allogeneic stem cell transplantation, and it is very difficult to treat steroid-resistant GVHD. Mesenchymal stem cells (MSCs) have a homing activity to inflammatory sites and modulate immune response via PGE2 and so on, suggesting that MSCs might be effective for refractory aGVHD. Recently, clinical studies have suggested that MSC infusion can also reduce the severity of GVHD. We report here the results of our multicenter phase I/II study of MSCs for treatment of steroid-resistant aGVHD.

Patients with steroid-resistant, grade II-IV, aGVHD were treated with MSCs derived from bone marrow of healthy volunteers and expanded in vitro (JR-031). MSCs were administered twice a week for 4 weeks. All patients received 2 × 10⁶ cells/kg of MSCs for each infusion. Patients with PR after 4 weeks were given continued weekly MSCs infusion for an additional 4 weeks.

From January 2009 to November 2010, 14 patients were treated. The median age was 52 years old (range: 4–62), Male (n=5) and Female (n=9). Nine patients were diagnosed as grade II aGVHD, 5 patients were diagnosed as grade III and no patients were diagnosed as grade IV aGVHD. Thirteen of 14 patients (92.9%) responded to MSCs, achieving CR (n=8) or PR (n=5) 4 weeks after treatment. Eleven patients (78.6%) survived 24 weeks after treatment. Seven patients showed severe adverse effects including thrombocytopenia, neutropenia and hepatic dysfunction, however, no patients had severe infections which was shown by existing salvage therapy for aGVHD.

The prognosis of steroid-resistant aGVHD was poor, and the most effective salvage therapy remains to be clarified. In this study, we showed that in vitro expanded MSCs, JR-031, might be a safe and effective salvage therapy for patients with steroid-resistant aGVHD.

Kato:Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japnese Ministry of Health, Labor and Welfare.: Research Funding.