title: Sufficient Immunosuppression with Thymoglobulin Is Essential for a Successful Haplo-Myeloid Bridge in Haploidentical-Cord Blood Transplantation.
abstract: In haploidentical (haplo)-cord blood (CB) transplantations, early haplo donor engraftment serves as a myeloid bridge to sustainable CB engraftment and is associated with early neutrophil recovery. The conditioning regimens as published for haplo-cord protocols usually contain serotherapy, such as rabbit antithymocyte globulin (ATG) (Thymoglobulin, Genzyme, Cambridge, MA). However, reducing or omitting serotherapy is an important strategy to improve early immune reconstitution after transplantation. The need for serotherapy in successful haplo-cord transplantation, defined as having a haplo-derived myeloid bridge to CB engraftment, has not been investigated before. Two consecutive cohorts of patients underwent transplantation with haplo-CB. The first group underwent transplantation with haplo-CB for active infection and/or an underlying condition with expected difficult engraftment without a conventional donor available. They received a single unit (s) CB and haplo donor cells (CD34(+) selected, 5 × 10(6) CD34(+)/kg). The second cohort included patients with poor-risk malignancies, not eligible for other treatment protocols. They received a sCB and haplo donor cells (CD19/αβTCR-depleted; 5 × 10(6) CD34(+)/kg). Retrospectively in both cohorts, active ATG (Thymoglobulin) levels were measured and post-hematopoietic cell transplantation area under the curve (AUC) was calculated. The influence of ATG exposure for having a successful haplo-myeloid bridge (early haplo donor engraftment before CB engraftment and no secondary neutropenia) and transplantation-related mortality (TRM) were analyzed as primary endpoints. Twenty patients were included (16 in the first cohort and 4 in the second cohort). In 58% of evaluable patients, there was no successful haplo-derived myeloid bridge to CB engraftment, for which a low post-transplantation ATG exposure appeared to be a predictor (P <.001). TRM in the unsuccessful haplo-bridge group was 70% ± 16% versus 12% ± 12% in the successful haplo-bridge group (P = .012). In conclusion, sufficient in vivo T depletion with ATG is required for a successful haplo-myeloid bridge to CB engraftment.
authors.affiliation: Pediatric Blood and Bone Marrow Program, University Medical Center Utrecht, The Netherlands. Electronic address: c.a.lindemans@umcutrecht.nl.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lindemans
authors.affiliation: Department of Hematology, University Medical Center Utrecht, The Netherlands; Tumorimmunology, Lab Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Liane C J
authors.initials: LC
authors.lastname: Te Boome
authors.affiliation: Pediatric Blood and Bone Marrow Program, University Medical Center Utrecht, The Netherlands; Tumorimmunology, Lab Translational Immunology, University Medical Center Utrecht, The Netherlands; Department of Pediatrics, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Department of Pharmacology, Leiden Academic center for Drug Research, University of Leiden, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Admiraal
authors.affiliation: Department of Pediatrics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Els C
authors.initials: EC
authors.lastname: Jol-van der Zijde
authors.affiliation: Virology, Deptartment of Medical Microbiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Wensing
authors.affiliation: Pediatric Blood and Bone Marrow Program, University Medical Center Utrecht, The Netherlands.
authors.forename: A Birgitta
authors.initials: AB
authors.lastname: Versluijs
authors.affiliation: Pediatric Blood and Bone Marrow Program, University Medical Center Utrecht, The Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Department of Hematology, University Medical Center Utrecht, The Netherlands; Tumorimmunology, Lab Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
authors.affiliation: Pediatric Blood and Bone Marrow Program, University Medical Center Utrecht, The Netherlands; Tumorimmunology, Lab Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
mesh_terms: D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D004306:Dose-Response Relationship, Immunologic; D023381:Endpoint Determination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D006239:Haplotypes / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000637:transplantation; D011817:Rabbits; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome; D061349:Unrelated Donors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; C512542:thymoglobulin
keywords: ATG; Engraftment; Haplo-cord transplantation; Infection; Thymoglobulin