Insurance approval of mesenchymal stem cell for acute GVHD in Japan: need of follow up for some remaining concerns.

Acute graft-versus-host disease (aGVHD) is a major obstacle following allogeneic hematopoietic stem cell transplantation. Steroid is the standard treatment for aGVHD grade II-IV; however, nearly half of patients do not respond to the therapy. Many drugs have been proposed, but no standard therapy has been determined. This is because of the resistance to these drugs and of infections due to prolonged immunosuppressive states. Over the past decade a new approach using mesenchymal stem cells (MSCs) has been emerging in Japan and western countries. MSCs have unique characteristics such as specific immunosuppressive properties, no immunogenicity on their own and supportive activity for hematopoiesis. Most of the published trials have reported a favorable effect in acute GVHD, but a phase III trial failed to reach the primary endpoint, although, subgroup analyses found significant effects on gut and liver GVHD in the patients with MSCs infusion. In Japan several institutes are trying to develop MSC for clinical use in post HSCT patients. However, several limitations make it difficult to use MSC in clinical practice. Recently we conducted a phase II/III study using MSC (JR-031) for patients with steroid-refractory grade III or IV aGVHD. From the feasible clinical results, JR-031 was approved by PMDA as the first product which meets the Act to Revise the Pharmaceutical Affairs Act and the Act to Ensure the Safety of Regenerative Medicine. The cost of one series of the treatment is more than ten million yen. Now we encounter new issues such as cost, indication, safety and efficacy. The mechanism of MSC is still unclear and potential concerns about ectopic tissue formation and MSC related malignancy in vivo remain. In conclusion, MSC infusions are well tolerated and show benefit in some patients without adverse safety effects; however, long-term follow-up is needed to be more certain of this.