The Impact of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Cyclosporine Concentration in Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation

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Cyclosporine A (CsA) is used as graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT). While polymorphisms in CYP3A4, CYP3A5, and ABCB1 genes influence CsA metabolism, their role in HSCT remains underexplored. We investigated the impact of these polymorphisms on CsA pharmacokinetics, early toxicity, and clinical outcomes in 86 leukemia patients undergoing HSCT (IR.TUMS.HORCSCT.REC.1402.07). CsA levels were monitored via radioimmunoassay, and genotyping for CYP3A4, CYP3A5, and ABCB1 polymorphisms was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Carriers of the rs2740574 (CYP3A4*1B, -392A>G) and the rs776746 (CYP3A5*3, 6986A>G) exhibited significantly higher mean trough concentrations compared to the wild-type genotypes (112.6 ± 52.1 versus 75.6 ± 31.0; p = 0.003, 126.1 ± 55.0 versus 89.5 ± 41.8; p < 0.001, respectively). No significant difference was observed for the rs1045642 variants. Both rs776746 and rs2740574 variants were associated with increased markers of nephrotoxicity and hepatotoxicity within 3 days post-HSCT. None of these polymorphisms showed significant associations with transplant outcomes. In conclusion, patients carrying rs776746 or rs2740574 achieved higher CsA trough levels and may require lower initial dosing. Future research should assess whether genotype-guided CsA dosing improves achieving therapeutic levels and reduces early toxicity or suboptimal immunosuppression post-HSCT.

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