PHARMACOGENETICS OF CALCINEURIN INHIBITORS IN HEMATOPOIETIC CELL TRANSPLANTATION: A SYSTEMATIC REVIEW

Objective: This systematic review aims to evaluate the influence of genetic polymorphisms on clinical outcomes in immunoprophylaxis with Calcineurin Inhibitors (CNIs) in patients undergoing hematopoietic cell transplantation. Materials and methods: Registered in PROSPERO on 09/03/2024 (CRD42024517094) and constructed following PRISMA 2020 guidelines, the review involved a comprehensive search across databases including PubMed, MEDLINE, LILACS, Bireme, Medcarib, Paho-iris, Wholis, Scopus, Web of Science, Embase, and Cochrane. The search limited to English articles published from 2013 to 2024, used terms related to “genetic polymorphisms”, “calcineurin inhibitors”, “hematopoietic cell transplantation”, “tacrolimus”, and “cyclosporine”, combined with Boolean operators. The last search was conducted on February 9, 2024. Inclusion criteria encompassed studies on humans addressing the pharmacogenetics of CNIs, while exclusion criteria included studies on other types of transplants and reviews. Results were saved in RIS format and analyzed using Rayyan platform by three independent reviewers. This study was supported by the CAPES Brazil ‒ Funding Code 001. Results and discussion: Out of 301 identified studies, 226 were screened after removing duplicates, and 19 were included. Most studies were from Asia (60%), followed by North America (35%) and Europe (5%). Among the included studies, 60% focused on tacrolimus (FK), 30% on cyclosporine (CSA), and 10% on both. The total patient number was 1,746, with 684 (39%) females and 1,062 males (60%). Age distribution varied: 60% adults, 20% pediatrics, and 20% both. Median ages were 52.5 (35‒61) for adults and 8.0 (6‒8) for pediatrics. Initial FK doses ranged from 0.01 mg/kg/day to 0.03 mg/kg/day, and CSA doses from 1.5 mg/kg/day to 3 mg/kg/day. The outcomes assessed were: 60% Pharmacokinetics (PK) of FK, 30% PK of CSA, and 10% both. FK PK was the most common outcome, assessed in 12 studies. Graft-Versus-Host Disease (GVHD) was analyzed in 9 studies (47%), and Acute Kidney Injury (AKI) was addressed in 6 studies (30%). Regarding genetic polymorphisms, key genes studied were: CYP3A5 (90%), ABCB1 (65%), CYP3A4 (45%), ABCC2 (15%), ABCG2 (10%), and ABCC1 (5%). The CYP3A5 3*/3* genotype was associated with higher FK levels and a higher concentration/dose (C/D) ratio, as well as a lower adjusted dose and increased AKI risk. Variants in ABCB1, such as C2677T, were linked to higher FK concentrations and increased toxicity risk, but ABCB1’s influence on CSA PK was not observed. The study of pediatric patients in China found that the clearance rate of CSA increased by 24.5% in carriers of the T allele of CYP3A4*1G compared to those with the CC allele. A French study has found polymorphisms in ABCC1, ABCC2, ATIC, and NFATC1 genes were strongly associated with severe a GVHD risk, with multiple SNPs indicating high disease severity risk. CYP3A5 and CYP3A4 genotypes and expression affect FK PK and dosing, with effects varying between intravenous and oral administration, and coadministration with antifungal azoles may increase toxicity in certain genotypes. Conclusion: This review highlights the significant impact of genetic polymorphisms on FK and CSA PK on effectiveness in hematopoietic cell transplantation, underscoring the need for personalized dosing approaches. Notable associations were found with CYP3A5, ABCB1, and CYP3A4 polymorphisms, among others, on implications for plasma levels and toxicity risks.