Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Matched and Single Antigen Mismatched Unrelated Bone Marrow Transplantation in Haemoglobinopathies Is Feasible and Leads to Early and Sustanined Engraftment with No Long-Term Toxicity or GvHD

Related haemopoietic stem cell transplantation is a well-established treatment modality for haemoglobinopathies, but it is limited by the availability of related donors. The results of unrelated transplantation have been variable with historical variable results, concern about GvHD and usually restricted to 10/10 matches. From 2011 to 2016 twelve consecutive unrelated bonemarrow transplants were conditioned with fludarabine 160 mg/m², treosulfan 42 g/m², thiotepa 10 mg/kg and ATG (Thymoglobulin) 11.25 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. 7 patients were transplanted for β thalassaemia major, one of α thalassaemia major and 4 for sickle cell disease. The median age was 9.5 years (2 - 17). The source of stem cells was BM in all patients: five 10/10 matched, six 9/10 matched and one 11/12 matched. The median cell dose was 3.01 x 10⁸ TNC/kg (range 1.53 - 11.07) and 4.27 x 10⁶ CD34+/kg (range 1.16 - 27.41). The median survival was 9.9 months (6.9-44.1). 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 achieved transfusion-independence and donor haematological values. No patient suffered primary or secondary graft failure. There was one death, one on day +257 due to idiopathic pneumonia syndrome in a patient with b thalassaemia major. Acute GvHD ≥ grade 2 occurred in 5 patients (41.7%). Chronic limited GvHD did not occur in any patient, but extensive occurred in the 5 patients developing acute GvHD. None of the patients had chronic GvHD at 18 months. VOD occurred in 4 patients (33.3%) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 13 days (range 9 to 22). Patient with sickle cell disease had the platelet count maintained >50 x 10⁹/L at all times. The median platelet engraftment >50 x 10⁹/L was 37 days (range 15 to 86) and >50 x 10⁹/L was 32 days (range 15 to 111). The median time to cessation of immunosuppression was 134 days (68-219).

Chimerism studies on day +28 demonstrated 100% in whole blood (WB) and 88.9% in T cells (T) >95%, and 0% WB and 11.1% T >50-89% [n=11]; day +90: 91.7% WB and 91.7% T >95%, 8.3% WB and 0% T >50-89%, 0% WB and 8.3% T <50% [n=12]; day +180: 91.7% WB and 91.7% T >95%, and 8.3% WB and 8.3% T >50-89% [n=12]; and day +365: 50% WB and 50% T >95%, 25% WB and 25% T >90-95%, and 25% WB and 25% T >50-89% [n=4].

In conclusion, unrelated bone marrow transplantation for all haemoglobinopathies is feasible and the overall survival and disease-free survival is 90.9%. FTTA leads to early and sustained engraftment with low rate of graft failure, and whilst the occurrence of VOD despite adequate chelation pre-transplantation and the incidence of GvHD was significant, these complications resolved with standard therapies and long-term outcomes approach those of related transplantation with no treatment required by 18 months.