Thiotepa in the Conditioning Regimen Decreases Rejection after HLA Identical Allogeneic Marrow Transplantation in Children with Beta Thalassemia Major Aged Less Then 4 Years

BMT in children with beta thalassemia major is the only form of definitive cure with correction of the genetic disease in a relevant proportion of patients, and long term thalassemia free survival. Lucarelli and coll. showed since 1986 that transplant performed early in the course of disease gives high chance of cure, and a system of class definition was reported in 1990 identifying as in class 1 patients without any evidence of organ damage, based on hepatomegaly, presence of liver fibrosis and history of regular or irregular iron chelation. Majority of children aged less then four years were then in class 1 and occasionally in class 2. Thiotepa has been introduced in the conditioning regimen of children less then 4 y.o. in the attempt to decrease the rejection rate in this category of good prognosis patients. Out of 519 children affected by not advanced Beta Thalassemia Major, either in class 1 or 2 of risk, with an HLA identical sibling donor, 25 patients aged 1 to 4 yo received an intensified conditioning regimen including thiotepa 10 mg/kg given in one day, in addition to standard BUS-CY regimen called PC 6. This was based on the observation that children aged below 4 transplanted after the standard PC 6 had significantly higher relapse rate with return to thalassemic pre transplant condition (OS, TFS, REJ were 87%; 86%; 4% vs 87%; 73%; 14% in children aged above or below 4 yo respectively (n=398 =>4; n=96 < 4). The increased relapse rate was more relevant in children treated with standard PC 6 and GVHD prophylaxis performed using short MTX plus CSA versus those who received cyclosporine alone. The GVHD prophylaxis protocol including sMTX + CSA +Pred, used after 1999 for all patients in our practice significantly improved OS, lowered GVHD rate, but had a trend toward increased rejection rate. This trend was more evident in children aged less than 4 despite an increased dose of Busulfan (16 mg/kg total) was already in use for younger children. Therefore, since 2003 we introduced Thiotepa for children less then 4 yo, maintaining the GVHD prophylaxis with sMTX and CSA. In the last group of 25 children aged below 4 receiving the intensified protocol, 1 patient rejected the graft and had thalassemia recovery, one died of GVHD and infection, and 23 are alive and cured. Actuarial probability of OS, TFS, Rejection were 96%; 91%, 5%. These results favourably compare to the previous results in this category of patients, confirming that Thiotepa exerts additional immunosuppressive and eradicating action, counteracting the effect of GVHD prophylaxis with sMTX+CSA, that exerts an action favouring rejection.