Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Related Transplantation in Haemoglobinopathies Leads to Early and Sustanined Engraftment with Low Incidence of VOD and GvHD

Haemopoietic stem cell transplantation is a well-established treatment modality for haemoglobinopathies. The challenge is to minimise graft failure due to the expanded haemopoietic compartment whilst reducing the risk VOD due to the effects of iron load. From 2011 to 2015 fifty-four consecutive sibling transplants were conditioned with fludarabine 160 mg/m², treosulfan 42 g/m², thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg (FTTA). Endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks. GvHD prophylaxis was provided with ciclosporin and MMF. 33 patients were transplanted for b thalassaemia major and 21 for sickle cell disease. The median age was 7 years (2 - 16). The source of stem cells was BM in 49 patients and mixed cord blood and BM in 5 patients. The median cell dose was 3.48 x10⁸ TNC/kg (range 0.23 - 8.51) and 6.73 x10⁶ CD34+/kg (range 1.3 - 14.72) for the patients receiving bone marrow only; 1.64 x10⁸ TNC/kg (range 1.22 - 3.9) and 4 x10⁶ CD34+/kg (range 2.06 - 8.79) for BM and 3.8 x10⁷ TNC/kg (range 0.8 - 7.32) and 0.53 x10⁶ CD34+/kg (range 0.06 - 1.8) for cord blood for the patients receiving a combination of cord blood and bone marrow. The median survival was 14.4 months (1-41.9). Patients with thalassaemia were Pesaro class I or II (Pesaro class III patients were intensively chelated pre-transplantation to return to class I or II). Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crises and/or acute chest syndrome not responding to hydroxycarbamide. All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥ 3.

All patients engrafted and achieved evidence of donor haemopoiesis on day +28, and all but one patient achieved transfusion-independence and donor haematological values. One patient (1.9%) had progressive reduction of donor haemopoiesis with reestablishment of ineffective thalassaemic haemopoiesis and transfusion dependence on day +313. There were two deaths, one on day +89 due to idiopathic pneumonia syndrome in a patient with b thalassaemia major and one on day +189 due to an intracranial haemorrhage caused by refractory immune thrombocytopenia off immunosuppression in a patient with sickle cell disease and moya moya. Acute GvHD ≥ grade 2 occurred in 6 patients (11.1%). Chronic limited GvHD occurred in 7 patients (13%) and extensive in 3 patients (5.6%). Chronic GvHD was only present at 18 months in one patient (1.9%). VOD occurred in 2 patients (3.7%, days +7 and +9 respectively) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 12 days (range 8 to 21). The median platelet engraftment >20 x10⁹/L was 27 days (range 15 to 73) and >50 x10⁹/L was 32 days (range 15 to 73). The median time to cessation of immunosuppression was 160 days (91-538).

Chimerism studies on day +28 demonstrated 92.3% in whole blood (WB) and 69% in T cells (T) >95%, 5.8% WB and 4.8% T >90-95%, 1.9% WB and 21.4% T >50-89%, 0% WB and 4.8% T <50%; day +90: 83.3% WB and 60.4% T >95%, 4.2% WB and 8.4% T >90-95%, 10.4% WB and 20.8% T >50-89%, 2.1% WB and 10.4% T <50%; day +180: 59.4% WB and 45% T >95%, 19% WB and 17.5% T >90-95%, 16.7% WB and 35% T >50-89%, 4.8% WB and 2.5% T <50%; and day +365: 59.4% WB and 53.4% T >95%, 12.5% WB and 13.3% T >90-95%, 15.6% WB and 20% T >50-89%, 12.5% WB and 13.3% T <50%.

In conclusion, FTTA leads to early and sustained engraftment with low rate of graft failure, and minimal occurrence of VOD whilst the incidence of GvHD is low.