Allogeneic bone marrow transplantation for fucosidosis.

Bone marrow transplantation was performed on an 8-month-old boy who was diagnosed as having fucosidosis following the diagnosis of the disease in his older brother. Although he was asymptomatic and his development was normal, abnomalities were found on an MRI scan prior to transplant. In the absence of a suitable related donor, an unrelated volunteer donor was used. Conditioning for the transplant consisted of busulphan and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of in vitro T cell-depletion of the bone marrow and in vivo administration of cyclosporin. The post-transplant period was complicated by moderately severe graft-versus-host disease. Engraftment was documented by the presence of donor levels of alpha-fucosidase, donor blood group and tissue type (difference in the DQ antigen), and chromosomal polymorphism pattern of donor origin. Eighteen months after transplant, there is evidence of mild neurodevelopmental delay. By contrast, his elder sibling showed far greater developmental delay at the same age. The patient's MRI scan shows improvement. We believe this to be the first case of human fucosidosis treated by bone marrow transplantation.

Bone marrow transplantation for Glanzmann's thrombasthenia.

Allogeneic matched bone marrow transplantation (BMT) was performed in a patient with type I Glanzmann's thrombasthenia, a rare, inherited bleeding disorder caused by a deficiency in the platelet membrane glycoprotein IIb-IIIa complex. The patient was a 2-year-old girl with a history of frequent hospitalisation. She was successfully transplanted with BM from her HLA-identical sibling. Engraftment was monitored by analysis of the platelet GPIIb-IIIa complex and by RFLP analysis using a minisatellite probe. Complete engraftment was seen at day +25. The patient has been clinically stable for 19 months. It is proposed that BMT is a suitable treatment for this condition where a matched, related donor is available and at an early stage, before the development of anti-platelet antibodies as a result of repeated transfusions.

Bone marrow transplantation for thalassaemia: experience of two British centres.

Bone marrow transplantation (BMT) was carried out on 38 patients with thalassaemia major over a period of 9 years; 30 were Asian. In all cases, the donor was an HLA-identical relative. The mean age at transplant was 6.4 years (range 0.5-20 years). Conditioning was busulphan and cyclophosphamide (CY). Cyclosporin (CsA) (n = 30), CsA + methotrexate (n = 6) or CsA + T cell depletion (n = 2) were used for prophylaxis against graft-versus-host disease (GVHD). Thirty-four patients successfully engrafted. Two patients required a second transplant and two achieved mixed chimerism, eventually rejecting their grafts. Nine patients (23.6) developed acute GVHD grade III-IV. Eleven patients (28.9) developed chronic GVHD. There were 11 deaths, 7 within the first 100 days post-BMT. Twenty-seven patients are alive from 156 to 3213 days post-BMT. The actuarial survival at 9 years post-BMT was 70%. The mortality is higher than in previously reported series; possible reasons for this are discussed.

Engraftment rates related to busulphan and cyclophosphamide dosages for displacement bone marrow transplants in fifty children.

The use of busulphan and cyclophosphamide permitted engraftment in 44 of 49 children receiving 'displacement' bone marrow transplants. Three patients who received T-cell-depleted marrow cells from HLA-haploidentical donors failed to engraft and other graft failures were due to inadequate induction dosage. Our standard schedule comprises busulphan 80 mg/m2/day x 4 days (adjusted if necessary to a minimum of 4 mg/kg/day or a maximum of 5 mg/kg/day) followed by cyclophosphamide 2 g/m2/day x 4 days but reduced so as not to exceed 75 mg/kg/day, a maximum dose preferred for patients with full marrows (e.g. those with thalassaemia major). Of 21 recipients of mixed lymphocyte culture (MLC)-negative donor marrow cells with full engraftment at 100 days, there were three late rejections. Of patients transplanted with marrow from MLC-positive donors, one had late rejection after cyclosporin A toxicity had necessitated withdrawal of the drug at day + 146 but six other patients, whose cyclosporin A was stopped routinely 1 year, remain well with full grafts. Ten patients died as a result of graft-versus-host disease. We are therefore exploring new approaches to T-cell depletion and storing autologous marrow for use in the event of graft failure. If necessary, a second transplant with busulphan and cyclophosphamide is best performed at 3 months after full recovery of the host. We conclude that elective transplants can be performed successfully in children with normal immune function without the need for irradiation.

Busulphan and cyclophosphamide cause little early toxicity during displacement bone marrow transplantation in fifty children.

Fifty children were induced with busulphan and cyclophosphamide before bone marrow transplantation. Our standard dose of cyclophosphamide was 2 g/m2 daily for 4 days, but this dosage was reduced if necessary so as not to exceed 75 mg/kg/day. A basal pulse rate that increased by more than 20 beats/min or a reduction in ECG voltage were indications for stopping cyclophosphamide. As a consequence, the fourth dose of cyclophosphamide was omitted for four children. One child died of cardiac arrest related to cyclophosphamide. We used busulphan at a dosage of 4 mg/kg/day for 4 days; neither 'busulphan lung' nor veno-occlusive disease occurred in any patient. The use of busulphan and cyclophosphamide did not guarantee freedom from interstitial pneumonitis, but this seemed to be related rather to the nature of prior treatment and the cytomegalovirus antibody status of the patient. Thus, we have developed a safe chemotherapy schedule for transplantation that avoids the need for radiotherapy and can, if necessary, be repeated after a 3-month interval.