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Biol Blood Marrow Transplant. 2015 May;21(5):900-5. doi: 10.1016/j.bbmt.2015.01.015. Epub 2015 Jan 21.

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.

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Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia. Electronic address:
Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
Pediatric Hematology-Oncology, Children's National Health System, Washington, District of Columbia.
Pediatric Hematology-Oncology, Medical University of South Carolina, Charleston, South Carolina.
Hematology-Oncology, All Children's Hospital, St. Petersburg, Florida.
Pediatric Hematology-Oncology, Tulane University Health Sciences Center, New Orleans, Louisiana.
Pediatric Hematology-Oncology, University of North Carolina, Chapel Hill, North Carolina.


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 200 mg/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.


Allogeneic hematopoietic cell transplantation; Sickle cell disease; Transplant conditioning

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