HLA- Matched Sibling Stem Cell Transplantation in Children with Thalassemia Major with ATG As Part of Preperative Regimen: A Suitable Choice Even for High Risk Cases

Background:Myeloablative chemotherapy using busulfan(BU) & cyclophosphamide(CY) is a standard form of conditioning for thalassemia transplantation. But this is associated with substantial incidence of graft rejection. This is much more common in high risk patients .

Methodology:This study retrospectively analyses the outcome of 50 (34 boys & 16 girls) consecutive children, who underwent HLA matched stem cell transplantation from family donors at our centre All patients were classified into 3 risk groups on the basis of inadequate chelation, hepatomegaly and the presence of portal fibrosis in the liver. Pesaro Class 1 patients had none of these, class 2 patients had one or two and class 3 had all three.30 patients received oral BU 1 mg/kg, Q6H for 4 days followed by CY 60 mg/kg/D for two days. & rabbit ATG (2.5 mg/kg/day from Day-5 to Day-1). Patients with advanced disease (class 3) received BU 0.8mg/Kg & CY 50 mg/kg. with same dose of ATG. All patients received stem cells harvested from G-mobilized bone marrow Standard MTX & Cyclosporin based GVHD prophylaxis , infection prophylaxis & supportive care as per standard protocols were given as per standard protocols. Chimerism was routinely monitored at 30, 60, 90, 120 and 365 days post transplant using PCR-based analysis of selected polymorphic STRs loci.

Results :OS and thalassemia-free-survival were estimated according to the Kaplan-Meier method. Probabilities of rejection, GVHD and infections were calculated by using the cumulative incidence estimator. The impact of the following parameters on OS and TFS was examined: (1) age of the recipient (above vs below the median value) (2) serum ferritin (above vs, the median value) (3) Pesaro class, (4) total nucleated cells per kg (contained in the graft) (above vs below the median), (5) CD34+ cells contained in the graft (above vs below the median) and (6) BU (oral vs i.v. BU). Both univariate and multivariate analysis of prognostic factors were made according to the log-rank test and to a stepwise Cox proportional hazards regression model, respectively. With a median follow-up of 11 years (range 1—17 years), the overall survival (OS) and thalassemia free survival (TFS) rates were 94% and 90%, respectively. The estimated TRM was 4% while the cumulative incidence of rejection/failure were 2%. One patient ( Class III, & HIV infection) died of severe veno-occlusive disease. ,The patient who rejected the graft after 10 months, received II transplant & is transfusion free with 98% donor chimerism post second transplant. The cumulative incidences of acute GVHD grade II & grade III were 15% & 8 %, respectively. 1 patient developed acute GVHD grade IV. None of the patients developed chronic GVHD. The estimated OS and TFS for patients with Class 1 and 2 disease according to Pesaro criteria were 94% and 92%, whereas for patients with Class 3 disease they were 90% and 85%, respectively.

Conclusions: Myeloablative( BU-CY) conditioning with ATG as conditioning from matched sibling donors with innovative modifications can be used to achieve excellent survival , with a low incidence of TRM and graft rejection in low as well as high risk patients.