Juan Eduardo Megías-Vericat

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 years 3 (OR: 1.41, 95% CI: 1.03–1.94) and 4–5 (OR: 1.42, 95% CI: 1.05–1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.

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 toward increased graft rejection (p = 0.05) was correlated to rs2066844 CC in NOD2/CARD15, a gene related to lymphocyte activation. CONCLUSION Pharmacogenetics can help identify patients at increased risk of clinical complications. Original submitted 30 January 2015; revision submitted 27 March 2015.

Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment

Abstract 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 toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Abstract 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 allele of ABCG2 rs2231142 was associated to greater cardiac (p = .004) and lung toxicities (p = .038). Delayed time to neutropenia recovery was observed with ABCB1 rs2032582 variant (p = .047). This study shows the impact of ABC polymorphisms in AML chemotherapy safety. Further prospective studies with larger population are needed to validate these associations.

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 patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed.

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

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 were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

Pharmacogenetics of metabolic genes of anthracyclines in acute myeloid leukemia

BACKGROUND Anthracyclines in combination with cytarabine have been the standard therapy for acute myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic pathway could be one of the causes of the interindividual differences in clinical outcomes. METHODS A systematic review of published studies in AML cohorts was carried out in order to analyze the influence of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity. RESULTS Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in the genes of carcinogens and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation and drug efficacy, influencing the survival rates and cardiac toxicities. In addition, genetic variability in the transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1) and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2). CONCLUSION The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.

Impact of novel polymorphisms related to cytotoxicity of cytarabine in the induction treatment of acute myeloid leukemia

Several novel single nucleotide polymorphisms (SNPs) involved in cytarabine cytotoxicity and related to clinical outcomes have been reported recently in a series of 232 pediatric patients with acute myeloid leukemia (AML). We report the first adult AML cohort in which the influence of these SNPs in cytarabine efficacy and toxicity was analyzed. Six of polymorphisms with clinical significance in the previous study [rs12036333, rs10758713, rs9883101, rs6550826, IRX2: rs2897047, mutated in colorectal cancers (MCC): rs7729269] were analyzed in a cohort of 225 adult patients at initial diagnosis of AML treated with an induction scheme of idarubicin plus cytarabine. The variant alleles of rs12036333 and rs10758713 confirmed the previous associations with lower survival rates. The minor alleles of rs9883101 and rs6550826 were also related to lower survival, in concordance with higher cytarabine-induced cytotoxicity observed in pediatric patients. However, discordant findings between AML adult and pediatric population were observed with IRX2 rs2897047, showing higher survival in heterozygous genotype carriers. The heterozygous genotype of MCC rs7729269 was associated with higher cytarabine-induced toxicities (renal, hepatic, lung, skin toxicities), whereas lower time to thrombocytopenia recovery was associated with the MCC rs7729269 minor allele. This study confirms the influence in survival rates of these polymorphisms in an adult AML population. Novel associations between MCC SNPs and cytarabine toxicities were reported and should be validated in prospective studies involving larger groups of patients.

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 induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA 99, 2007 and 2010 trials). The efficacy of the first induction cycle was evaluated comparing complete remission (CR) versus partial remission (PR) or resistance (patients dying during induction excluded), and overall survival (OS), event free survival (EFS), disease free survival (DFS) and relapse free survival (RFS) at 5 years. Genotypes were studied with the co-dominant model. Association between variables was assessed using logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, haemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R V.3.1.2). The Kaplan–Meier method and Cox proportional were used for survival estimates. Results Median age of patients was 51.1 years (16–78). The variant allele of DCK SNP rs2306744, the enzyme that catalyses the limiting first phosphorylation in the activation of cytarabine, showed higher CR (OR 6.2; 95% CI 1.3–30.2; p=0.024). CDA is the main inactivating enzyme of cytarabine. The variant allele of rs602950 was related to higher CR (OR 3.0; 95% CI 1.02–8.8; p=0.045), OS (HR 1.7; 95% CI 1.03–2.6; p=0.039) and EFS (HR 0.4; 95% CI 0.2–0.7; p=0.014). However, the heterozygous genotype of CDA rs2072671 was associated with lower OS (HR 2.2; 95% CI 1.2–4.1; p=0.015), EFS (HR 1.9; 95% CI 1.01–3.4; p=0.045), DFS (HR 3.8; 95% CI 1.2–12.4; p=0.027) and RFS (HR 9.1; 95% CI 1.2–68.6; p=0.032), and heterozygous genotype of CDA rs3215400 with lower DFS (HR 2.9; 95% CI 1.4–6.3; p=0.006) and RFS (HR 3.3; 95% CI 1.1–9.9; p=0.033). The variant allele of RRM1 (rs9937), the enzyme directly associated with cytarabine sensitivity, was associated with lower OS (HR 2.0; 95% CI 1.1–3.5; p=0.021) and RFS (HR 3.8; 95% CI 1.02–14.3; p=0.047). Conclusion This study revealed the influence on cytarabine efficacy of DCK, CDA and RRM1 polymorphisms in AML adult patients, previously suggested in other studies. Further studies with a larger population are needed to validate these associations. References and/or acknowledgements Megías-Vericat JE, et al. Pharmacogenomics2016doi: 10.2217/pgs-2016-0055. No conflict of interest