Long-Term Follow-up of Patients with Chronic Granulomatous Disease Receiving Bone Marrow Transplantation Using Immunosuppressive Conditioning Regimen

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by a mutation of one of 5 subunits of the nicotinamide adenine dinucleotide phosphate oxidase and resulting in the impairment of microbial activity of phagocytes. The disease is characterized by recurrent and severe infections of bacterial and fungal origin and a high rate of inflammatory bowel disease. Recently, the prognosis of CGD patients has been improved by the earlier diagnosis, management of infectious complications, and application of allogeneic hematopoietic stem cell transplantation (HSCT). However, allogeneic HSCT in patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality.

In Hiroshima University Hospital, 38 patients with CGD underwent bone marrow transplantation (BMT) with immunosuppressive conditioning regimen since 2004. All patients with CGD suffered from recurrent and severe infections and/or intractable inflammatory bowel disease. The age of 38 patients at the time of BMT was 2 to 40 years. Six patients over 15 years old were died from GVHD and transplant-related complications.

In this study we report our single-center results of long-term follow-up of 11 survivals with CGD who underwent BMT from 2004 to 2009. All 11 patients with CGD were 91-phox deficiency. The age of 11 patients at the time receiving BMT was 4 to 28 years. Seven patients were over 20 years of age, and 4 patients were 7 to 9 years, respectively. The conditioning regimen consisted of fludarabine, cyclophosphamide, 3 to 3.6 Gy of total body irradiation, melpharan, and/or antithymoglobulin. Bone marrow cells were obtained from 5 HLA-matched, 1 -mismatched related, 4 HLA-matched and 1 -mismatched unrelated donors, respectively. Acute GVHD of grade I - II developed in 4 of 11 patients. Three cases occurred in patients given transplants from unrelated donors, one from HLA-matched elder sister. All patients have exhibited 100% of complete myeloid donor chimerism and cleared all infectious and inflammatory complications. Ten of 11 patients have shown 100% of performance status without any medical supports. Four adolescent patients have been to junior

or senior high school students with complete cure. Four adulthood patients fathered children 3 to 6 years after BMT. The wives of 3 patients naturally conceived, implying the successful preservation of patients' fertility. One has a child by the artificial fertilization using his frozen sperm before BMT. Only a patient who underwent BMT from HLA-matched elder sister has been suffering from chronic GVHD followed by cryptogenic organizing pneumonia. He has engaged in deskwork with 90% of Karnofsky performance status. These results suggest that BMT using immunosuppressive conditioning regimen is safe and effective for the successful transplantation followed by the improvement of quality of life for CGD patients.