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Author Notes:

Correspondence and reprint requests: John Horan, MD, MPH, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, 1405 Clifton Road, Atlanta, GA 30322. E-mail address: jdgsfhoran@gmail.com.

E. O. S. and K.-Y. C. are co-first authors. L. K. and J. H. are co-senior authors.

There are no conflicts of interest to report.

Subjects:

Research Funding:

This work was supported by the ACTSI KL2-Mentored Clinical and Translational Research Program (to E.O.S.) and the National Institutes of Health grant KL2TR000455 (to E.O.S.).

Keywords:

  • Alefacept
  • Conditioning
  • Hematopoietic stem cell transplantation
  • Nonmalignant diseases
  • Rejection
  • Anemia, Aplastic
  • Antigens, CD2
  • Blood Component Transfusion
  • Bone Marrow Transplantation
  • Child
  • Cord Blood Stem Cell Transplantation
  • Dyskeratosis Congenita
  • Fanconi Anemia
  • Female
  • Graft Survival
  • Graft vs Host Disease
  • Historically Controlled Study
  • Humans
  • Immunologic Memory
  • Immunophenotyping
  • Infant
  • Killer Cells, Natural
  • Lymphocyte Depletion
  • Male
  • Pilot Projects
  • Recombinant Fusion Proteins
  • T-Lymphocyte Subsets
  • Transplantation Conditioning
  • Unrelated Donors

Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases

Tools:

Journal Title:

Biology of Blood and Marrow Transplantation

Volume:

Volume 21, Number 10

Publisher:

, Pages 1845-1852

Type of Work:

Article | Final Publisher PDF

Abstract:

Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days −40 and −9 and .5 mg/kg/dose on days −33, −26, −19, and −12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor–based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2hi/CCR7−/CD45RA− effector memory (Tem) and CD2hi/CCR7+/CD45RA− central memory (Tcm) CD4+ and CD8+ T cells with relative preservation of the CD2lo Tem and Tcm subpopulations. In addition, depletion of CD2+ natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.

Copyright information:

© 2015 American Society for Blood and Marrow Transplantation.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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