0000000000115532
AUTHOR
Luis Rojas
Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy.
Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations…
Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: a systematic review and meta-analysis
Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: a systematic review and meta-analysis
Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment
Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxici…
Association of SNPs with the efficacy and safety of immunosuppressant therapy after heart transplantation.
Aim: Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation. Materials & methods: In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year. Results: The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations. Lower renal function levels were found in patients with rs9282564 AG (p = 0.003), related to higher blood cyclosporine blood levels. A tendency tow…
Meta-analysis and systematic review of the effect of the donor and recipient CYP3A5 6986A>G genotype on tacrolimus dose requirements in liver transplantation
Objective A meta-analysis was carried out of publishedstudies on the effect of the CYP3A5 6986A>Gpolymorphism in liver donors and transplant recipientson tacrolimus pharmacokinetics.Methods Cohort studies that evaluated the relationshipbetween the CYP3A5 polymorphism in liver donors andtransplant recipients and tacrolimus, trough bloodconcentration normalized for the daily dose (C) perkilogram body weight (D) (C/D, ng/ml/mg/kg/day) up to1 year after transplantation, were included. Data were notrestricted by patient age or the language or journal ofpublication. A literature search was conducted using theCochrane Library, MEDLINE, EMBASE, and grey literature,and articles published up to 24 Ap…
SNPs and taxane toxicity in breast cancer patients
Aim: In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed. Patients & methods: Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel). Results: Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p ≤ 0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p ≤ 0.01). Conclusion: Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cance…
PKP-020 Impact of nadph oxidase functional polymorphisms in acute myeloid leukaemia induction chemotherapy
Background NADPH oxidase, a key mediator of oxidative cardiac damage and remodelling, modulates anthracycline clinical cardiotoxicity. Purpose Single nucleotide polymorphisms (SNPs) of NADPH oxidase genes could lead to interindividual differences in treatment outcome in acute myeloid leukaemia (AML) patients. Material and methods The main three NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112 and RAC2:rs13058338) were evaluated in 225 adult patients at the initial diagnosis of AML using a mass spectrometry based multiplex genotyping assay (Sequenom). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA 99, 2007 and 2010 trials). The efficacy…
A systematic review and meta-analysis of the impact of WT1 polymorphism rs16754 in the effectiveness of standard chemotherapy in patients with acute myeloid leukemia
The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR: 1.24, 95% CI: 1.06-1.45, P = 0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and …
PKP-003 Influence of cytarabine metabolic pathway polymorphisms in effectiveness of acute myeloid leukaemia induction treatment
Background Cytarabine is considered the most effective chemotherapeutic agent in the treatment of acute myeloid leukaemia (AML). Purpose Several studies suggest that single nucleotide polymorphisms (SNPs) in genes involving the metabolic pathway of cytarabine could influence treatment outcomes, although their clinical relevance remains undetermined. Material and methods The SNPs of cytarabine pathway (DCK:rs2306744, rs11544786, rs4694362; CDA:rs2072671, rs3215400, rs532545, rs602950; NT5C2:rs11598702; RRM1:rs9937; NME1:rs2302254) were evaluated in 225 adult patients at initial diagnosis of AML using a mass spectrometry based multiplex genotyping assay (Sequenom). All patients received induc…
PKP-005 Prognostic impact of novel gene polymorphisms in newly diagnosed acute myeloid leukaemia adults undergoing induction chemotherapy: Abstract PKP-005 Table 1
Background Single nucleotide polymorphisms (SNPs) could lead to inter-individual differences in treatment outcomes. Purpose A recent study 1 reported several novel SNPs involved in cytarabine cytotoxicity using a whole-genome approach, which were associated with clinical outcomes in a paediatric AML population. However their association with effectiveness and toxicity remain undetermined in adults. Material and methods The six SNPs with clinical significance in the Gamazon study 1 (Table 1) were evaluated in 109 adult patients at initial diagnosis with AML using a mass spectrometry–based multiplex genotyping assay (Sequenom). All patients were treated with idarubicin plus cytarabine. Genoty…
Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: A systematic review and meta-analysis of observational studies
The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at year…
Impact ofABCsingle nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia
Anthracycline uptake could be affected by efflux pumps of the ABC family. The influence of 7 SNPs of ABC genes was evaluated in 225 adult de novo acute myeloid leukemia (AML) patients. After multivariate logistic regression there were no significant differences in complete remission, though induction death was associated to ABCB1 triple variant haplotype (p = .020). The ABCB1 triple variant haplotype was related to higher nephrotoxicity (p = .016), as well as this haplotype and the variant allele of ABCB1 rs1128503, rs2032582 to hepatotoxicity (p = .001; p = .049; p .001). Furthermore, the variant allele of ABCC1 rs4148350 was related to severe hepatotoxicity (p = .044), and the variant al…
Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies
The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expre…