Fludarabine/Treosulfan/Thiotepa/ATG Conditioning Leads to Earlier Engraftment and Higher Donor Chimerism Than Busulfan/Cyclophosphamide, and Enables the Use of Mismatched and Unrelated Donors for Transplantation in Haemoglobinopathies

Abstract 3234 Haemopoietic stem cell transplantation is the only proven curative treatment available for haemoglobinopathies. From 2000 to 2010 severty-four consecutive transplants were conditioned with busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab (Bu/Cy) achieving a DFS of 94.5%. In order to reduce busulfan toxicity, minimise mixed chimerism and enable the use of related mismatched and unrelated donors, the conditioning regimen was modified: fludarabine 160 mg/m 2 , treosulfan 42 g/m 2 , thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg or 11.25 mg/kg (FTTA). 18 patients [13 with β thalassaemia major and 5 with sickle cell disease, median age 6.5 years (2 – 16)] received a related transplant: fifteen 10/10 matched sibling, one 10/10 matched related and two 9/10 mismatched sibling. The source of stem cells was BM in 16 patients and mixed cord blood and BM in 2 with a median cell dose of 3.85 ×10 8 TNC.kg (range 1.50 – 6.87). Median follow-up was 6.7 months (2.40 – 20). Two patients received an unrelated transplant (α thalassaemia major, 12 years, 10/10 matched BM, 2.4 ×10 8 TNC/kg, survival +5 months; sickle cell disease, 7 years, 9/10 matched PBSC, 6 ×10 6 CD34+/kg, survival +1.8 months). Endogenous haemopoiesis was suppressed with hypertransfusions. GvHD prophylaxis: ciclosporin and MMF. Patients with thalassaemia were Pesaro class I or II. Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crisis and/or acute chest syndrome not responding to hydroxycarbamide. All patients are alive with transfusion-independence and donor haematological values (DFS 100%, OS 100%). Acute GvHD ≥grade 2 occurred in 1 related patient (5.6%) and both unrelated patients; chronic limited GvHD in 2 related patients (11.1%), all with resolution following steroid treatment. Neutrophil engraftment was achieved at a median of 12 days (9 – 21) in comparison to 19.5 days (12 – 28 days) with the previous protocol. Chimerism studies in whole blood demonstrated that donor haemopoiesis was higher for FTTA v Bu/Cy at all-time points (day +28: 100% >95% for FTTA v 81.4% >95%, 16% >90–95% and 2.4% >50–80%; day +90: 91.6% >95% and 8.3% >90–95% v 67.1% >95%, 12.8% >90–95%, 12.8% >80–90% and 12.8% >50–80%; day +150: 50% >95%, 37.5% >90–95% and 12.5% >50–80% v 55.8% >95%, 10.8% >90–95%, 14.7% >80–90%, 8.8% >50–80%, 2.9% >30–50% and 2.9% >20–30%). Donor T-cell lymphopotiesis is FTTA was day +28: 100% (68 – 100), day +90: 98.5% (55–100) and day +150: 98% (73–100). In conclusion, FTTA leads to earlier engraftment and higher donor chimerism than Bu/Cy, no graft failure, and enables the use of mismatched and unrelated donors for transplantation in haemoglobinopathies, whilst the incidence of GvHD is low. Disclosures: No relevant conflicts of interest to declare.