The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases

Graft-versus-host disease (GVHD), graft rejection, disease recurrence and long-term toxicity remain significant obstacles to successful allogeneic bone marrow transplantation (BMT) in children with genetic diseases. In an attempt to improve results, we used a preparative regimen consisting of three alkylating agents, busulfan (BU), thiotepa (TTP) and cyclophosphamide (CY), for T cell-depleted allogeneic bone marrow transplantation instead of the conventional BU-CY protocol. The effect of this intensified regimen was investigated in 26 consecutive children with genetic diseases who underwent T cell-depleted BMT from HLA-identical siblings. Sixteen patients were males and 10 females, of median age 5 (0.2-14) years. The diseases included β-thalassemia major, osteopetrosis, severe combined immunodeficiency, Wiskott-Aldrich syndrome, familial agranulocytosis, congenital idiopathic hemolytic anemia (CIHA), Gaucher's disease, Niemann-Pick disease, Hurler's syndrome, and adrenoleukodystrophy. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was as expected, with WBC > 1.0 x 10⁹/l at day +19 (10-33), ANC > 0.5 x 10⁹/l at day +22 (10-56) and platelets > 25 x 10⁹/l at day +32 (18-131). Transplant-related mortality was 19%. Overall survival and disease-free survival (DFS) at 60 months follow-up were both 77%. Our results with the BU-TTP-CY regimen followed by T cell-depleted BMT in genetic diseases may provide a basis for prospective comparison with the standard conditioning regimen of BU-CY in the management of children suffering from these conditions.