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CTLA-4 polymorphisms: influence on transplant-related mortality and survival in children undergoing allogeneic hematopoietic stem cell transplantation

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Abstract

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.

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Author information

Correspondence to Bernd Gruhn.

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Conflict of interest

The authors have no potential conflicts of interest to declare.

Ethical standard

All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study has been approved by the Jena University Hospital Ethics Committee (5154-05/17). Informed consent was obtained from all individual participants or the responsible persons included in the study.

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Hammrich, J., Wittig, S., Ernst, T. et al. CTLA-4 polymorphisms: influence on transplant-related mortality and survival in children undergoing allogeneic hematopoietic stem cell transplantation. J Cancer Res Clin Oncol 144, 587–592 (2018). https://doi.org/10.1007/s00432-018-2578-8

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Keywords

  • CTLA-4
  • Single nucleotide polymorphism
  • Allogeneic hematopoietic stem cell transplantation
  • Children
  • Transplant-related mortality