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Approximately 80% of children with severe thalassemia (thal) were cured with hematopoietic stem cell transplantation (HSCT). However, initial reports suggested that a subset of patients (pts) had poorer outcomes, and were more likely to experience transplant-related mortality or recurrence. These were older pts who had evidence of organ damage from iron-overload and were classified as class 3 Lucarelli pts. One approach to reduce the mortality that has been tested in limited series is reduced intensity (RI) HSCT, which relies upon immunosuppressive rather than ablative pre-transplantation conditioning to facilitate engraftment of donor cells. We conducted RIHSCT in 8 severe thal pts with class 3 lucarelli. All were older than 10 yrs of age (median 12.5 yrs; range 10 – 18) and received blood more than 100 transfusions. Three pts had homozygous β thalassemia and 4 had β thalassemia/hemoglobin E. Five of these pts had splenectomy. The conditioning regimen; busulfan 12 mg/kg orally, iv. fludarabine 175–180 mg/m2, antithymocyte globulin (ATG) (Fresineus®) 40 mg/kg, was given in all pts. In addition, one pt (pt 2) also received thiotepa 10 mg/kg and single fraction total lymphoid irradiation (TLI) 500 cGY and one (pt 1) also received. TLI. All pts received hydroxyurea 20 mg/kg at least for 6 months prior to transplant in order to suppress erythroid expansion. Seven pts received peripheral blood stem cells (PBSC) from 6 HLA antigens matched siblings and 1 (Pt2) received T cell depleted PBSC by CD34+ selection from 4 HLA antigens matched mother. The median number of infused CD34+ cell was 9 × 106cells/kg (range 6.5 – 15 × 106). GvHD prophylaxis regimen was with cyclosporin or tracolimus and MMF. All pts can achieve full donor engraftment. Median time of neutrophil engraftment was 11 days (range 11– 14), and platelet was 14 days (range 12–24). Two pts did not have neutrophil count less than 0.5 × 109/L and four did not have platelet count less than 20 × 109/L. Four pts did not have acute GvHD, 3 had gr I and 1 had gr II. Only 1 pt had limited chronic GvHD. All pts had no major toxicity except pt 2 who developed CMV retinitis but it was resolved. The 2 yr thal free survival rate is 88% (95%CI: 39 %, 98 %) and the 2 yr overall survival rate is 100%. The median time of follow up was 10 months (range: 3 – 63). Currently, 6 pts had full donor chimerism, one had mixed chimerism and one had graft rejection. We would like to suggest that busulfan, fludarabine, and ATG together is the backbone of RIHSCT conditioning regimen for class 3 lucarelli pts. Since 2 (pt 7 and pt 8) out of three pts who did not have splenectomy prior to transplant, had mixed chimerism and one of these 2 pts finally had graft rejection, we, therefore, plan to add either another agent such as thiotepa or melphalan or TLI in our backbone RIHSCT conditioning regimen for the pts who do not have splenectomy prior to transplant in the future to achieve the sustainable engraftment. Donor chimerism study, Recent outcome, and Follow up time Pt Day + 15 Day + 30 Day + 60 Day + 100 Recent Outcome F/U time (months) 1 M F F F A with F 63 2 F F F F A with F 47 3 F F F F A with F 39 4 F F F F A with F 12 5 F F F F A with F 8 6 F F F F A with F 7 7 F M L L A with L 4 8 F F M N/A A with M 3 M = mixed chimerism, F = full donor chimerism, L = loss of donor chimerism, A = alive, F/U = follow up, N/A = not applicable