Allogeneic stem cell transplantation as treatment for heavily treated, refractory acute graft-versus-host disease after HLA-mismatched stem cell transplantation.

No effective treatment has been established for patients with steroid-refractory acute graft-versus-host disease (GVHD). Recently, we demonstrated in a murine tandem bone marrow transplantation model that life-threatening GVHD established by the first bone marrow transplantation was successfully treated by engraftment of a second donor graft after reduced-intensity conditioning. We named the effect by which allografts counteract GVHD "graft-versus-GVHD." To investigate the efficacy of graft-versus-GVHD treatment clinically, 16 patients who developed, after human leukocyte antigen-mismatched stem cell transplantation, severe GVHD, refractory to three to five lines of GVHD-specific treatments, underwent 17 allogeneic stem cell transplantations using reduced-intensity conditioning regimens with grafts from a second donor. Among the 15 transplantations that could be evaluated, rescue donor grafts were engrafted in 11 cases and rejected in 4 cases. For patients who achieved rescue donor engraftment, the response rate was 90.9% (eight complete response, two partial response, and one stable disease). Six of the eight patients with complete response survived without GVHD symptoms, with a median follow-up of 2128 days. No new development of GVHD by the second graft was observed. No patients had recurrence of the original malignant disease. In contrast, no long-term survivors were observed in patients who rejected rescue donor grafts. We propose here a novel graft-versus-GVHD treatment to treat refractory GVHD, and these results strongly suggest that GVHD can be successfully treated by eliminating the harmful lymphocytes responsible for GVHD by a second allogeneic stem cell transplantation.

Ikegame K ，Yoshihara S ，Taniguchi Y ，Kaida K ，Inoue T ，Okada M ，Taniguchi K ，Hasei H ，Tamaki H ，Fujioka T ，Kato R ，Soma T ，Ogawa H ... -  《-》

Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.

Petersen SL 《-》

Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning.

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe.

Baron F ，Lechanteur C ，Willems E ，Bruck F ，Baudoux E ，Seidel L ，Vanbellinghen JF ，Hafraoui K ，Lejeune M ，Gothot A ，Fillet G ，Beguin Y ... -  《-》

CD6+ T cell depleted allogeneic bone marrow transplantation from genotypically HLA nonidentical related donors.

Soiffer RJ ，Mauch P ，Fairclough D ，Alyea E ，Anderson K ，Fisher D ，Freedman A ，Bartlett-Pandite L ，Robertson M ，Schlossman R ，Gollob J ，Marcus K ，Murray C ，Kuhlman C ，Freeman A ，Nadler L ，Ritz J ... -  《BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION》

Unmanipulated HLA 2-3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning.

Ogawa H ，Ikegame K ，Yoshihara S ，Kawakami M ，Fujioka T ，Masuda T ，Taniguchi Y ，Hasei H ，Kaida K ，Inoue T ，Kim EH ，Kawase I ... -  《BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION》