Impact of Genetic Variants in Cyclophosphamide-Metabolizing Enzymes on Clinical Outcomes After Haploidentical Hematopoietic Stem Cell Transplantation

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) followed by post-transplant cyclophosphamide (CPA) treatment is an avenue to expand the pool of potential donors. This study aimed to investigate whether the gene polymorphisms related to CPA activation and metabolism are associated with the clinical outcomes of patients receiving haplo-HSCT. METHODS: Genomic DNA from 35 haplo-HSCT patients were subject to analysis of 34 genetic polymorphisms located in CYP2B6, CYP2C19, ALDH1A1, ALDH3A1, GSTA1, GSTP1, GSTM1, and GSTT1 genes. The association of these gene polymorphisms with the occurrence of graft-versus-host disease (GVHD), relapse, and survival status of patients were analyzed by chi-square or Fisher's exact test under five genetic models, logistic regression analysis, and cumulative hazard curve analysis. RESULTS: Age, gender, conditioning regimens, and the use of phenytoin were not associated with the clinical outcomes post-haplo-HSCT. Five SNPs in CYP2B6 (rs3745274 and rs8192719), CYP2C19 (rs 4244285 and rs3758580), and ALDH3A1 (rs2228100) genes were associated with chronic GVHD (cGVHD), acute GVHD (aGVHD) grade I-II, and GVHD, respectively. No SNPs were linked to survive or relapse. Logistic regression analysis adjusting for the use of phenytoin and conditional regimens and cumulative hazard curve analysis further demonstrated that rs375274 in the CYP2B6 gene was associated with the development of cGVHD, while rs222810 in the ALDH3A1 gene was associated with the development of aGVHD and aGVHD I-II for patients receiving haplo-HSCT. CONCLUSIONS: This study highlights the impacts of genetic polymorphisms related to CPA bioactivation and metabolism on the clinical outcomes of haplo-HSCT with post-transplant CPA. Despite the limited sample size and retrospective nature, identifying risk loci to enhance the transplant success rates for patients receiving haplo-HSCT is warranted.