title: 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.
abstract: 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.
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia. Electronic address: jdgsfhoran@gmail.com.
authors.forename: John T
authors.initials: JT
authors.lastname: Horan
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Ann
authors.initials: A
authors.lastname: Haight
authors.affiliation: Pediatric Hematology-Oncology, Children's National Health System, Washington, District of Columbia.
authors.forename: Jacqueline Lagerlof
authors.initials: JL
authors.lastname: Dioguardi
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Clark
authors.initials: C
authors.lastname: Brown
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Audrey
authors.initials: A
authors.lastname: Grizzle
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Chiani
authors.initials: C
authors.lastname: Shelman
authors.affiliation: Pediatric Hematology-Oncology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Julie
authors.initials: J
authors.lastname: Kanter
authors.affiliation: Hematology-Oncology, All Children's Hospital, St. Petersburg, Florida.
authors.forename: Greg
authors.initials: G
authors.lastname: Hale
authors.affiliation: Hematology-Oncology, All Children's Hospital, St. Petersburg, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Nieder
authors.affiliation: Pediatric Hematology-Oncology, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Melody
authors.initials: M
authors.lastname: Benton
authors.affiliation: Pediatric Hematology-Oncology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kasow
authors.affiliation: Pediatric Hematology-Oncology, Children's National Health System, Washington, District of Columbia.
authors.forename: Allistair
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Aflac Cancer and Blood Disorders Center, Emory University/Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Kuang-Yueh
authors.initials: KY
authors.lastname: Chiang
mesh_terms: D000293:Adolescent; D064591:Allografts; D000755:Anemia, Sickle Cell / Q000628:therapy*; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D002066:Busulfan / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019172:Transplantation Conditioning / Q000379:methods*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000961:Antilymphocyte Serum; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: Allogeneic hematopoietic cell transplantation; Sickle cell disease; Transplant conditioning