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.
Keywords: Allogeneic hematopoietic stem cell transplantation; CTLA-4; Children; Single nucleotide polymorphism; Transplant-related mortality.