title: Impact of serotherapy on immune reconstitution and survival outcomes after stem cell transplantations in children: thymoglobulin versus alemtuzumab.
abstract: The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly affected by the kinetics of reconstitution of the immune system. This study compared the effects of antithymocyte globulin (ATG) and alemtuzumab on various outcome parameters after HSCT. The study cohort consisted of 148 children, with a median age of 9.6 years (range, .4 to 19.0), who underwent HSCT for malignant and benign hematological disorders in a single HSCT unit. Conditioning included ATG (n = 110) or alemtuzumab (n = 38). Cox proportional hazard regression analysis showed that alemtuzumab significantly delayed the recovery of CD3(+) T cells and CD4(+)as well as CD8(+) T cell subsets (P ≤ .001) and natural killer (NK) cells (P = .008) compared with ATG. In both ATG- and alemtuzumab-treated patients, shorter drug exposure lead to significantly faster recovery of T cells. Alemtuzumab was associated with lower donor chimerism 3 and 6 months after transplantation and a higher risk of disease relapse (P = .001). The overall survival and event-free survival risks were significantly lower for alemtuzumab-treated patients (P = .020 and P < .001, respectively). Patients who received alemtuzumab showed a trend to lower risk of acute graft-versus-host disease, more human adenovirus, and less Epstein-Barr virus reactivations compared with patients who received ATG. These data indicate that children treated with alemtuzumab as part of the conditioning regimen have a slower T cell and NK cell reconstitution compared with those treated with ATG, which compromises the overall and event-free survival. Prolonged length of lympholytic drug exposure delayed the T cell recovery in both ATG- and alemtuzumab-treated patients. Therefore, we recommend detailed pharmacokinetic/pharmacodynamic (PK/PD) analyses in a larger cohort of patients to develop an algorithm aiming at optimization of the serotherapy containing conditioning regimen.
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Willemsen
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: c.m.jol-van_der_zijde@lumc.nl.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Jol-van der Zijde
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Pediatric Blood and Marrow Program, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Admiraal
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anja M
authors.initials: AM
authors.lastname: Jansen-Hoogendijk
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ostaijen-Ten Dam
authors.affiliation: Departments of Clinical Genetics and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.affiliation: Pediatric Blood and Marrow Program, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Kesteren
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacqueline L M
authors.initials: JL
authors.lastname: Waaijer
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.affiliation: Pediatric SCT Unit and Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
mesh_terms: D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D064591:Allografts; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D012189:Retrospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D000074323:Alemtuzumab; C512542:thymoglobulin
keywords: Alemtuzumab; Antithymocyte globulin; Children; Hematopoietic stem cell transplantation; Immune reconstitution; Survival