title: Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors.
abstract: CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype.
authors.affiliation: Servei d'hematologia, Institut Català d'Oncologia, Hospital Josep Trueta, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bosch-Vizcaya
authors.forename: Arianne
authors.initials: A
authors.lastname: Pérez-García
authors.forename: Salut
authors.initials: S
authors.lastname: Brunet
authors.forename: Carlos
authors.initials: C
authors.lastname: Solano
authors.forename: Ismael
authors.initials: I
authors.lastname: Buño
authors.forename: Vicent
authors.initials: V
authors.lastname: Guillem
authors.forename: Carolina
authors.initials: C
authors.lastname: Martínez-Laperche
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sanz
authors.forename: Cristina
authors.initials: C
authors.lastname: Barrenetxea
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.forename: Esperanza
authors.initials: E
authors.lastname: Tuset
authors.forename: Natàlia
authors.initials: N
authors.lastname: Lloveras
authors.forename: Rosa
authors.initials: R
authors.lastname: Coll
authors.forename: Ramon
authors.initials: R
authors.lastname: Guardia
authors.forename: Yolanda
authors.initials: Y
authors.lastname: González
authors.forename: Josep M
authors.initials: JM
authors.lastname: Roncero
authors.forename: Anna
authors.initials: A
authors.lastname: Bustins
authors.forename: Santiago
authors.initials: S
authors.lastname: Gardella
authors.forename: Cristalina
authors.initials: C
authors.lastname: Fernández
authors.forename: Joan
authors.initials: J
authors.lastname: Buch
authors.forename: David
authors.initials: D
authors.lastname: Gallardo
mesh_terms: D000293:Adolescent; D000328:Adult; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006648:Histocompatibility; D006801:Humans; D008297:Male; D008875:Middle Aged; D035781:Siblings; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D060908:CTLA-4 Antigen