CYP3A5基因多态性对异基因造血干细胞移植患者他克莫司血药浓度和不良事件的影响 The effect of CYP3A5 gene polymorphism on tacrolimus concentration and adverse events in patients undergoing allogeneic hematopoietic stem cell transplantation
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ABSTRACT: 目的
探讨在异基因造血干细胞移植（allo-HSCT）患者中，CYP3A5基因多态性与他克莫司血药浓度及急性移植物抗宿主病（GVHD）间的关系。 方法
回顾性分析2019年7月至2020年2月在中国医学科学院血液病医院接受allo-HSCT的35例中国成人患者。移植前采集骨髓进行CYP3A5基因分型。应用静脉输注他克莫司、短疗程甲氨蝶呤（MTX）±吗替麦考酚酯进行GVHD预防。在他克莫司用药第2天或第3天监测初始血药浓度，随后每周监测2～3次。根据目标血药浓度（10～15 ng/ml）调整药物剂量。 结果
16例携带CYP3A5*3/*3基因的allo-HSCT患者的初始他克莫司血药浓度（9.82 ng/ml对8.53 ng/ml）、初始血药浓度/剂量（C/D）比值（5.72 ng·ml−1·mg−1对4.26 ng·ml−1·mg−1）、allo-HSCT后第一和第二周C/D比值中位数（5.29 ng·ml−1·mg−1对4.61 ng·ml−1·mg−1，5.65 ng·ml−1·mg−1对4.56 ng·ml−1·mg−1）均明显高于19例至少携带一个CYP3A5*1等位基因的患者（P值分别为0.028、0.001、0.037、0.045）。至少携带一个CYP3A5*1等位基因的患者，allo-HSCT后Ⅲ～Ⅳ级急性GVHD的发生率有高于携带CYP3A5*3/*3基因患者的趋势［（26.3±10.1）％对（6.2±6.1）％，P＝0.187］。 结论
CYP3A5基因型导向给药可能有助于allo-HSCT后更快地达到他克莫司目标血药浓度，减少严重急性GVHD的发生，改善移植疗效。
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PROVIDER: S-EPMC8607024 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.
| S-EPMC10800424 | biostudies-literature
Project description:Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2-3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.
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Project description:CYP3A5 gene polymorphism in recipients plays an important role in tacrolimus blood pharmacokinetics after renal transplantation. Even though CYP3A5 protein is expressed in renal tubular cells, little is known about the influence on the tacrolimus intrarenal exposure and hence graft outcome. The aim of our study was to investigate how the tacrolimus intrarenal concentration (Ctissue) could be predicted based on donor CYP3A5 gene polymorphism in renal transplant recipients. A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. Seventy-four renal biopsy specimens were obtained at 3 months and 1 year after transplantation to determine the donor CYP3A5 polymorphism and measure the Ctissue by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The tacrolimus Ctissue ranged from 52 to 399 pg/mg tissue (n = 74) and was weak but significantly correlated with tacrolimus trough concentration (C0) at 3 months after transplantation (Spearman, r = 0.3560, p = 0.0096). No significant relationship was observed between the donor CYP3A5 gene polymorphism and Ctissue or Ctissue/C0. These data showed that the tacrolimus systemic level has an impact on tacrolimus renal accumulation after renal transplantation. However, donor CYP3A5 gene polymorphism alone cannot be used to predict tacrolimus intrarenal exposure. This study may be valuable for exploring tacrolimus renal metabolism and toxicology mechanism in renal transplant recipients.
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Project description:PurposeTo analyze factors influencing tacrolimus (TAC) trough concentration (C0) in β-thalassemia major (β-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with β-TM. Furthermore, to analyze the correlation between TAC C0 and efficacy and adverse reactions.Patients and methodsProspectively collection of demographic information and details of combined treatment of patients with β-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C0. The impact of different genotypes and the co-administration of azole antifungal drugs on β-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C0.ResultsA total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C0/Div. Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C0/Dpo. Group comparisons showed that voriconazole can affect TAC C0 administered intravenously (IV) and orally in β-TM pediatric patients, while patient genotype can affect TAC C0 during oral administration. TAC C0 does not correlate with aGVHD or liver injury, but infection may be associated with TAC C0.ConclusionThe concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C0 is not suitable as an indicator of the efficacy of TAC.
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Project description:BackgroundTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).Design and methodsTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.ResultsThirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.ConclusionsCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.
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Project description:Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122-2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627-4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as GVHD prophylaxis.
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Project description:The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT). This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant differences and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis between both groups to non-MDRO colonized control cohorts (2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4% versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than their paired non-MDRO-colonized cohort. Conversely, there was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2% respectively, p=0.24) between the FMT-MDRO group and their paired non-MDRO cohort. Collectively, these data suggest that negative clinical outcomes, including mortality associated with MDRO colonization, may be ameliorated by pre-HCT FMT, even in the absence of intestinal MDRO decolonization. Further work is needed to explore this observed benefit.
| S-EPMC8430254 | biostudies-literature
Project description:BackgroundHigh intensity treatments such as hematopoietic cell transplantation (HCT) can be curative for patients with hematologic malignancies, but this needs to be balanced by the high risk of nonrelapse mortality (NRM) during the first 2 years after HCT. Sarcopenia (low muscle mass) is associated with physical disability and premature mortality in individuals with nonmalignant diseases and may be a predictor of NRM and poor overall survival in patients undergoing HCT.MethodsThis was a retrospective cohort study of 859 patients with acute leukemia or myelodysplastic syndrome who underwent a first HCT as adults (≥18 years) between 2007 and 2014. Sarcopenia was assessed from pre-HCT abdominal computed tomography scans. Two-year cumulative incidence of NRM was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained and adjusted for relevant covariates. Kaplan-Meier method was used to examine overall survival. All statistical tests were two-sided.ResultsMedian age at HCT was 51 years (range = 18-74 years); 52.5% had a high [≥3] HCT-comorbidity index; 33.7% had sarcopenia pre-HCT. Sarcopenia was an independent predictor of higher NRM risk (hazard ratio = 1.58, 95% CI = 1.16 to 2.16) compared with patients who were not. The 2-year incidence of NRM approached 30% in patients with sarcopenia and high (≥3) HCT-comorbidity index. Patients with sarcopenia had on average a longer hospitalization (37.2 days vs 31.5 days, P < .001) and inferior overall survival at 2 years (55.2%, 95% CI = 49.5% to 61.0% vs 66.9%, 95% CI = 63.0% to 70.8%, P < .001).ConclusionsSarcopenia is an important and independent predictor of survival after HCT, with potential additional downstream impacts on health-economic outcomes. This information can be used to facilitate treatment decisions prior to HCT and guide interventions to decrease the risk of treatment-related complications after HCT.
| S-EPMC6695315 | biostudies-literature
Project description:ObjectivesTacrolimus is characterized by high pharmacokinetic variability in combination with a narrow therapeutic range. However, influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio (GRWR) on tacrolimus' pharmacokinetics after pediatric living donor liver transplantation (LDLT) remains unclear.MethodsA total of 174 LDLT recipients (<6 y) were grouped according to donor CYP3A5 genotypes (nonexpressor (NEX) or expressor (EX)) and GRWR (<3.0% (SS, small-size) or ≥3.0% (LS, large-size)): SS/NEX (n = 40), SS/EX (n = 38), LS/NEX (n = 48), and LS/EX (n = 48). Pharmacokinetics of tacrolimus and clinical outcomes were analyzed.ResultsThe relationships between the concentration-dose ratio and donor CYP3A5 genotypes and graft size were examined 3, 7, 14, and 30 days after the transplantation. Tacrolimus C0 levels varied greatly among groups, although recipients started with the same initial dosage. LS/EX recipients had significantly lower C0 levels in comparison with those of other groups. The use of CYP3A5-EX-grafts and a greater GRWR both resulted in significantly higher TAC dose requirements and lower C/D ratios. However, the significance of GRWR no longer exists 3 months after transplantation. The multivariate generalized linear mixed model analysis showed that donor CYP3A5 genotypes (F = 11.876; P = 0.01) and GRWR (F = 4.631; P = 0.033) were independent impact factors for C/D ratios 3, 7, 14, and 30 days after transplantation. Donor CYP3A5-EX genotype was associated with significantly increasing risks of infectious complications and significantly lower Cylex ATP values. However, no significant difference was observed in acute rejections among 4 groups.ConclusionsMonitoring of C0 levels alone is not reliable to guide tacrolimus administration. Donor CYP3A5 and GRWR both significantly affect tacrolimus pharmacokinetics after pediatric LDLT. The use of Cylex ATP tests would be helpful to avoid overimmunosuppression.
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Project description:PurposeCognitive impairment is common and consequential in patients with cancer who undergo allogeneic hematopoietic stem cell transplantation (HSCT). However, there is no standard of care for evaluating cognition in patients prior to or after receiving HSCT, and it is not known which patients are at highest risk for cognitive impairment. The objectives of this study were to describe cognitive function in patients prior to allogeneic HSCT and identify demographic, disease-related, and psychosocial factors associated with cognitive function.MethodsPrior to HSCT, participants completed the Montreal Cognitive Assessment (MoCA). We assessed bivariable associations between continuous MoCA scores and demographic, disease-related, and psychosocial variables using linear regression. Variables significant at the p < 0.2 level were adjusted for age, sex, and years of education in multiple linear regression analyses.ResultsOver 50% of participants demonstrated evidence of cognitive impairment (MoCA < 26) prior to transplantation. When adjusted for demographic variables, two characteristics were significantly associated with worse cognitive function: the hematopoietic cell transplantation-comorbidity index score (p = 0.01) and history of alcohol or substance abuse (p = 0.02). Pre-HSCT cancer and cancer treatment-specific variables were not associated with cognitive function.ConclusionCognitive impairment is common in patients scheduled to receive HSCT. Pre-transplantation evaluation of medical comorbidities and history of substance abuse may be important in identifying patients at risk for cognitive impairment. Further research characterizing the trajectory and impact of cognitive impairment on patient symptom burden and function may help improve outcomes.
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