Successful Bone Marrow Transplantation with an Intensively Immunosuppressive Conditioning with Low Toxicity for High-Risk Chronic Granulomatous Disease Patients.

Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent bacterial and fungal infections, often resulting in impaired quality of life and death. Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative therapy for patients with CGD. HSCT in certain CGD patients is associated with a significant risk of therapy-related morbidity due to toxicity, rejection, GVHD, and/or infectious complications. Recently successful HSCT with nonmyeloablative conditioning for CGD patients has been developed. However, the results of HSCT in adult CGD patients have been insufficient in adult patients with CGD. In this study 5 patients with adult CGD underwent bone marrow transplantation after undergoing an intensive immunosuppressive regimen with reducing toxicity and optional donor lymphocyte infusion (DLI). All patients were diagnosed by the absence of oxidase activity and confirmed by the lack of the expression of 91^phox using monoclonal antibody by flow cytometry. All patients were more than twenty years of age and suffered from critical and life-threatening infections, such as brain abscess, osteomyelitis, and granulomatous colitis at transplantation. Patients underwent a conditioning regimen consisting of cyclophosphamide (30 mg/Kg × 4), fludarabine (30 mg/m² × 5), anti-lymphocyte globulin (15 mg/Kg × 4), and low-dose (3 Gy) of total body irradiation. Four of five patients were transplanted from HLA-identical siblings and one patient from HLA-haploidentical brother presenting microchimerism between donor and recipients. After transplantation prompt engraftment with mixed chimerism was observed without severe conditioning-related complications in all patients. Their infections were immediately improved within one month after transplantation during the period of mixed chimerism. The degree of chimerism was serially assessed by microsatellite DNA sequences and by the presence of 91^phox-positive neutrophils using flow cytometry. Based on the chimerism assay, DLI was performed in two patients without developing GVHD. All patients have achieved complete chimerism without therapy-related complications. These results using an intensively immunosuppressive conditioning with low toxicity is a promising treatment modality for high-risk patients with CGD.