title: Busulfan, fludarabine, and alemtuzumab as a reduced toxicity regimen for children with malignant and nonmalignant diseases improves engraftment and graft-versus-host disease without delaying immune reconstitution.
abstract: For children receiving allogeneic hematopoietic stem cell transplants (HSCTs), the toxicity of the conditioning regimen and graft failure remain challenges. We previously reported that targeted i.v. busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG) decreased toxicity but had a graft failure rate of 21%. To improve the engraftment rate, we replaced ATG with alemtuzumab, a monoclonal Ab targeting CD52. Thirty-five children with malignant and nonmalignant diseases were enrolled in this phase II prospective study. Twelve children had HLA-matched related donors (MRDs), 16 had 10 of 10, and 7 had 9 of 10 HLA allele-matched unrelated donors (MUDs). Thirty-one of 34 evaluable patients (91%) achieved a durable engraftment. All 3 patients who rejected had a nonmalignant disease and received a MUD transplantation (2 mismatched at 1 antigen). Three patients died of a transplantation-related complication (9% ± 5.2%). Seven patients had disease relapse or progression, 2 of whom died. At a median follow-up of 35 months (range, 15-85 months), the event-free survival (EFS) was 61% ± 9.0% and the overall survival (OS) was 78% ± 7.5%. The median time to neutrophil recovery, B cell, and T cell reconstitution were 16 days, 3 months, and 6 months, respectively. At 1 year, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 subsets were 97%, 87%, 100%, and 99%, respectively. Six patients (17% ± 6.6%) developed acute graft-versus-host disease (aGVHD), only 2 of which were >grade II. Two patients (8% ± 5.4%) progressed to chronic GVHD (cGVHD). These results suggest that replacement of rATG with alemtuzumab may improve engraftment as well as decrease cGVHD rates without resulting in delays in immune reconstitution.
authors.affiliation: Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Law
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.forename: Lisa
authors.initials: L
authors.lastname: Musick
authors.forename: Janel R
authors.initials: JR
authors.lastname: Long-Boyle
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Baxter-Lowe
authors.forename: Biljana
authors.initials: B
authors.lastname: Horn
mesh_terms: D000293:Adolescent; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D002066:Busulfan / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D009504:Neutrophils / Q000276:immunology; D011446:Prospective Studies; D055502:Secondary Prevention; D012720:Severity of Illness Index; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019653:Myeloablative Agonists; D000074323:Alemtuzumab; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine