Full Donor Engraftment without Chronic GvHD Following HLA-Matched Sibling Donor Haemopoietic Stem Cell Transplantation for Diamond Blackfan Anaemia

Long-term survival in Diamond Blackfan Anaemia (DBA) is compromised by transfusional iron overload and/or side effects of high-dose steroids as well as increasing recognition of the increased risks of aplasia and malignancy. Allogeneic haemopoietic stem cell transplantation (HSCT) can cure the haematological manifestations of DBA, but the optimal conditioning protocol is yet to be defined, particularly avoiding irradiation in view of the increased risk of malignancy. Four consecutive children with DBA were conditioned with oral busulfan 14 mg/kg (days-9 to -6), cyclophosphamide 200 mg/kg (days-5 to -2) and horse ALG 45 mg/kg (days-4 to -2) prior to HLA-matched sibling donor HSCT. Graft-versus-host disease (GvHD) prophylaxis was provided with ciclosporin from day-1 for six months to a target range of 100–150 ng/mL and methotrexate 10 mg/m² on days +4 and +7.

• P1: 10 years old boy who was transfusion dependent for two years having lost the response to steroids. In addition, he had deafness, short stature, gastrooesophageal reflux and cleft palate. He received bone marrow (8 × 10⁸ TNC/kg).

• P2: 10 years old boy who was steroid dependent and had developed diffuse liver steatosis and bone fractures. In addition, he had short stature and undescended testis. He received bone marrow (1.91 × 10⁸ TNC/kg).

• P3: four year old girl who was transfusion dependent with no associated abnormalities. She received a combination of cord blood (0.83 × 10⁷ TNC/kg) and bone marrow (0.738 × 10⁸ TNC/kg) from a sibling born following pre-implantation genetic diagnosis and HLA typing.

• P4: six year old boy born at 34 weeks of gestation who was transfusion dependent. He received a combination of cord blood (1.4 × 10⁷ TNC/kg) and bone marrow (2.73 × 10⁸ TNC/kg).

Neutrophil and platelet engraftment were prompt in all 4 patients (neutrophils: day 15–22; platelets day 10–33). Stable complete donor haemopoiesis was confirmed in all four patients using peripheral blood genomic DNA microsatellites markers by genescanning on day +28, 6 months and 1 year post-transplantation. The conditioning protocol was well tolerated by all patients with no life-threatening infections, though one patient had moderate veno-occlusive disease responding to defibrotide followed by gastrointestinal haemorrhage and another suffered reversible ciclosporin-associated posterior leucoencephalopathy and stage IV, steroid-responsive, acute gut GvHD. All four patients are alive with full donor haemopoiesis and normal haematological parameters at 11, 12, 15 and 24 months post-transplantation. Sibling allogeneic HSCT with this non-TBI protocol is a reasonable and feasible option for DBA patients suffering from unacceptable steroid side effects or chronic transfusion therapy.