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

Abstract

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 × 4 days (−8 to −5), TTP 5 mg/kg × 2 days (−4 and −3), and CY 60 mg/kg × 2 days (−2 and −1). Engraftment was as expected, with WBC >1.0 × 10⁹/l at day +19 (10–33), ANC >0.5 × 10⁹/l at day +22 (10–56) and platelets >25 × 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.