RESUMO
OBJECTIVE: Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is still linked to a poor prognosis. Mainly, donor`s T-cells mediate the graft-versus-leukemia effect. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule which down-regulates T-cell activation. Single nucleotide polymorphism (SNP) in CTLA-4 may have an effect on immune response. METHODS: Eighty-eight children with acute leukemia and their donors were genotyped of CTLA-4 gene for rs231775. We searched for an association of CTLA-4 SNP with relapse and survival after allogeneic HSCT. RESULTS: We identified a significantly reduced relapse rate in children who received a transplant from a donor with the CTLA-4 genotypes AG or GG in comparison with genotype AA of rs231775 (19% vs 40%, P = 0.026). In addition, we observed a significant difference in event-free survival (EFS) depending on the donor´s genotype. The EFS was 70% or 46% if the patient was transplanted from a donor with CTLA-4 genotype AG/GG or AA, respectively (P = 0.025). In multivariate analysis, CTLA-4 genotype was an independent risk factor for relapse rate (P = 0.028). CONCLUSION: This study suggests that CTLA-4 polymorphism rs231775 is relevant for relapse and survival after allogeneic HSCT in childhood and should be further investigated in clinical trials.
Assuntos
Alelos , Antígeno CTLA-4/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Biomarcadores Tumorais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Prognóstico , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for a variety of hematological diseases; however, it is still associated with substantial morbidity and mortality. Transplant-related mortality (TRM) after HSCT depends mainly on the toxicity of the conditioning regimen, infections, and graft-versus-host disease. The purpose of this study was to identify the association between CTLA-4 single nucleotide polymorphisms and TRM in children undergoing allogeneic HSCT. METHODS: 153 donors and 153 children with acute lymphoblastic leukemia, acute myeloid leukemia or juvenile myelomonocytic leukemia who had undergone allogeneic HSCT were genotyped of CTLA-4 gene for rs3087243 (CT60G>A), rs231775 (+ 49 A>G) and rs4553808 using TaqMan real-time polymerase chain reaction. RESULTS: We observed a significant association between the donor's CLTA-4 genotype of rs3087243 and TRM in children undergoing allogeneic HSCT. Genotype AG was found in 78 donors (51%), GG in 44 donors (29%) and 31 donors (20%) were homozygous for AA. 30 patients died as a result of transplant-related causes. Interestingly, we observed a significantly reduced TRM in children who were transplanted from a donor with the CTLA-4 genotype GG in comparison to genotype AG or AA (9 versus 19 versus 36%, P = 0.013). In addition, we found significant differences of event-free survival (EFS) depending on the donor's genotype. The EFS was 64, 46 or 32% if the patient was transplanted from a donor with CTLA-4 genotype GG, AG or AA, respectively (P = 0.043). In multivariate analysis, CTLA-4 genotype of rs3087243 was an independent risk factor for TRM (P = 0.011) and EFS (P = 0.035). CONCLUSION: This study provides first evidence that the CTLA-4 polymorphisms are significant risk factors for TRM and survival in children undergoing allogeneic HSCT and should be evaluated in further trials.