title: Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity.
abstract: Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with myeloid malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m(2)) with targeted myeloablative Bu (90 mg·h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.
authors: Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
authors: I H
authors: IH
authors: Bartelink
authors: Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: E M L
authors: EM
authors: van Reij
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: C E
authors: CE
authors: Gerhardt
authors: Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: E M
authors: EM
authors: van Maarseveen
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: A
authors: A
authors: de Wildt
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: B
authors: B
authors: Versluys
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: C A
authors: CA
authors: Lindemans
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: M B
authors: MB
authors: Bierings
authors: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands; U-DANCE, Section Tumorimmunology, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: j.j.boelens@umcutrecht.nl.
authors: Jaap Jan
authors: JJ
authors: Boelens
mesh_terms: D000257:Adenoviridae Infections / Q000401:mortality; D000293:Adolescent; D002066:Busulfan / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000401:mortality; D019337:Hematologic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D019349:Roseolovirus Infections / Q000401:mortality; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: Busulfan; Fludarabine; Hematopoietic cell transplantation; Pediatrics