title: Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases.
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 CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) 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.
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Stenger
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Kuang-Yueh
authors.initials: KY
authors.lastname: Chiang
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Ann
authors.initials: A
authors.lastname: Haight
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Muna
authors.initials: M
authors.lastname: Qayed
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, Washington.
authors.forename: Leslie
authors.initials: L
authors.lastname: Kean
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia. Electronic address: jdgsfhoran@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Horan
mesh_terms: D000077944:Alefacept; D000741:Anemia, Aplastic / Q000628:therapy; D016913:Blood Component Transfusion / Q000706:statistics & numerical data; D016026:Bone Marrow Transplantation; D018801:CD2 Antigens / Q000276:immunology; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D019871:Dyskeratosis Congenita / Q000628:therapy; D005199:Fanconi Anemia / Q000628:therapy; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D065386:Historically Controlled Study; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007223:Infant; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D010865:Pilot Projects; D011993:Recombinant Fusion Proteins / Q000600:supply & distribution / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D019172:Transplantation Conditioning; D061349:Unrelated Donors
chemical_list: D018801:CD2 Antigens; D011993:Recombinant Fusion Proteins; D000077944:Alefacept
keywords: Alefacept; Conditioning; Hematopoietic stem cell transplantation; Nonmalignant diseases; Rejection