Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: Results of a dose de-escalation trial

Academic Article


  • High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day+28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.
  • Authors

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    Author List

  • Horan JT; Haight A; Dioguardi JL; Brown C; Grizzle A; Shelman C; Kanter J; Hale G; Nieder M; Benton M
  • Start Page

  • 900
  • End Page

  • 905
  • Volume

  • 21
  • Issue

  • 5