title: Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen.
abstract: Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens are increasingly used for the hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases. Early experience suggests that these regimens are associated with good survival but a high incidence of mixed chimerism, which we have previously shown to be influenced by the alemtuzumab schedule. We hypothesized that the underlying diagnosis and donor graft source would also affect the development of mixed chimerism and that the majority of patients would survive RIC HCT without graft loss. To examine this, we conducted a retrospective study of 206 patients with metabolic diseases, non-Fanconi anemia marrow failure disorders, and primary immune deficiencies who underwent 210 consecutive RIC HCT procedures at Cincinnati Children's Hospital. Ninety-seven percent of the patients engrafted. Mixed donor and recipient chimerism developed in 46% of patients. Patients with marrow failure had a low risk of mixed chimerism (hazard ratio [HR], .208; 95% confidence interval [CI], .061 to .709; P = .012). The risk of mixed chimerism was high in patients who received a cord blood graft (HR, 3.122; 95% CI, 1.236 to 7.888; P = .016). As expected, patients who received a proximal or higher dose per kilogram of alemtuzumab schedule also experienced higher rates of mixed chimerism (all HR > 2, all P < .05). At the time of last follow-up (median, 654 days; range, 13 to 3337), over 75% of patients had greater than 90% whole blood donor chimerism. A second transplantation was performed in 5% of patients. Three-year survival without retransplantation was 84% (95% CI, 71% to 98%) for patients who underwent transplantation with an HLA-matched sibling donor. Survival without retransplantation was negatively affected by lack of a matched related donor, increasing age, and development of grades III and IV acute graft-versus-host disease. We conclude that alemtuzumab, fludarabine, and melphalan RIC HCT offers good results for many patients and that the risk of developing mixed chimerism is influenced by underlying diagnosis, graft source, and alemtuzumab dosing.
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Rebecca.Marsh@cchmc.org.
authors: Rebecca A
authors: RA
authors: Marsh
authors: Division of Epidemiology and Biostatistics, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors: Marepalli B
authors: MB
authors: Rao
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Aharon
authors: A
authors: Gefen
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Denise
authors: D
authors: Bellman
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Parinda A
authors: PA
authors: Mehta
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Pooja
authors: P
authors: Khandelwal
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Sharat
authors: S
authors: Chandra
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Sonata
authors: S
authors: Jodele
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Kasiani C
authors: KC
authors: Myers
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Michael
authors: M
authors: Grimley
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Christopher
authors: C
authors: Dandoy
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Javier
authors: J
authors: El-Bietar
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Ashish R
authors: AR
authors: Kumar
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Tom
authors: T
authors: Leemhuis
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Kejian
authors: K
authors: Zhang
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Jack J
authors: JJ
authors: Bleesing
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Michael B
authors: MB
authors: Jordan
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Alexandra H
authors: AH
authors: Filipovich
authors: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Stella M
authors: SM
authors: Davies
mesh_terms: D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D046528:Chimerism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan
keywords: Alemtuzumab; Bone marrow transplantation; Hematopoietic cell transplantation; Mixed chimerism; Primary immune deficiency; Reduced-intensity conditioning