José Luis Poveda

In Utero Exposure to Mycophenolate Mofetil : A Characteristic Phenotype?

Mycophenolate mofetil (MMF) is a widely prescribed immunosuppressive agent after solid organ transplantation. Potential teratogenic effects after in utero exposure to MMF in experimental studies and clinical observations in humans has been postulated in recent literature. However, a specific pattern of malformation has not been identified yet. We present a newborn patient, born to a recipient of renal transplantation, who became pregnant while taking MMF as immunosuppressive therapy. The newborn exhibited cleft lip and palate, bilateral microtia and atretic external auditory canals, chorioretinal coloboma, hypertelorism, and micrognathia. An extensive review of the literature documented six other cases with similar malformations after in utero exposure to MMF. A consistent pattern of malformations comprising cleft lip and palate, microtia and external auditory canals could be observed in five of the six cases. A different malformative pattern observed in one of the patients could be attributed to a different agent rather than MMF. The possible teratogenic effects of other immunosuppressive drugs, such as tacrolimus and prednisone, to which this patient was also exposed, are discussed herein. In addition, the differential diagnosis with other dysmorphic syndromes that can present with a similar phenotype, such as CHARGE syndrome, 18q deletion and hypertelorism‐microtia‐clefting (HMC) syndrome, is presented. We conclude that in utero exposure to MMF can cause a characteristic phenotype and propose the existence of a mycophenolate‐associated embryopathy whose main features are: cleft lip and palate, microtia with atresia of external auditory canal, micrognathia and hypertelorism. Ocular anomalies, corpus callosum agenesis, heart defects, kidney malformations, and diaphragmatic hernia may be part of the phenotypic spectrum of MMF embryopathy. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed.

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 cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

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 published studies on the effect of the CYP3A5 6986A>G polymorphism in liver donors and transplant recipients on tacrolimus pharmacokinetics. Methods Cohort studies that evaluated the relationship between the CYP3A5 polymorphism in liver donors and transplant recipients and tacrolimus, trough blood concentration normalized for the daily dose (C) per kilogram body weight (D) (C/D, ng/ml/mg/kg/day) up to 1 year after transplantation, were included. Data were not restricted by patient age or the language or journal of publication. A literature search was conducted using the Cochrane Library, MEDLINE, EMBASE, and grey literature, and articles published up to 24 April 2013 were selected. Data were pooled (random-effects model), and the results were expressed as the mean difference of the corresponding C/D ratios and 95% confidence intervals. Results Six studies involving donor genotypes (254 patients) and four involving recipient genotypes (180 patients) were ultimately included. The meta-analysis showed the C/D ratio to be significantly higher in recipients with nonexpresser donor variants at all time points. In recipients, the variant did not influence the C/D ratio. Conclusion The presence of the CYP3A5 6986A>G polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although only the evidence available for the first month after transplantation was of adequate quality for demonstrating a significant difference. The evidence provided here shows no effect of the recipient genotype; however, the quality of the evidence was low, thereby precluding the drawing of firm conclusions.

Treatment adherence and other patient-reported outcomes as cost determinants in multiple sclerosis: a review of the literature

Background Treatment adherence is one of the key factors for achieving optimal clinical outcomes. In order to assess costs related to adherence to, and persistence and compliance with, disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS), a narrative review of the literature was performed. Satisfaction with and preference for DMTs and their delivery devices were also assessed, as both can have an influence on patients’ adherence and persistence. Methods Electronic databases (MEDLINE, PubMed, Google Scholar, congress proceedings) were searched to identify publications analyzing MS costs related to adherence, persistence, satisfaction, and preferences for MS treatments. Bibliographic references were hand searched. English or Spanish studies published between January 2007 and January 2013 were selected. Results A total of 398 titles were identified, of which 12 met the inclusion criteria. Six studies evaluated the impact of adherence, persistence, and compliance on treatment costs; four publications analyzed satisfaction with DMTs; and two assessed treatment preferences based on attributes of the delivery device. Increased adherence and persistence were associated with better clinical outcomes, leading to lower relapse risk (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.59–0.85) and a decrease in health care resource use, such as MS-related hospitalizations (OR: 0.63; 95% CI: 0.47–0.83) and emergency department visits (OR: 0.80; 95% CI: 0.60–1.07). This reduction in resource use led to a patient/year total cost reduction (excluding DMT costs) of up to 22%. Conclusion This review highlights the importance of ensuring adequate adherence in MS patients through treatments and devices better tailored to patients’ needs that could enhance clinical outcomes and reduce MS costs. Understanding the factors underlying satisfaction and compliance with treatment and patients’ preference for certain therapies could help in the development of strategies that can improve adherence.

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.

Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation

Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation.

Paclitaxel and Carboplatin Treatment for Advanced Ovarian Cancer during Pregnancy

Ovarian carcinoma during pregnancy is a rare event that should be treated. In these cases, due to the lack of information available, doubts about the safety of mother and fetus are present. In this report, a 42-year-old woman who was diagnosed with a stage III ovarian carcinoma received six cycles of chemotherapy with carboplatin and paclitaxel from the 16th until 36th week of gestation. At 38 weeks, a normal male baby was born. There were no abnormalities during birth and during a 2-month follow-up period. This case adds to the available literature and supports the use of these chemotherapy agents during pregnancy, if the risk-benefit balance is appropriate.

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.