Virginia Bosó

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.

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 expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

Mycophenolate Mofetil During Pregnancy: Some Words of Caution

I TRANSPLANT REGISTRIES have accounted for more than 14 000 deliveries in solid organ transplant recipient women up to 2002; thus, the possibility of becoming pregnant has been considered an additional benefit of organ transplantation.1 Improvement in organ transplantation outcome has been linked with the development of more effective immunosuppressive drugs. Hence, in recent years new pharmacologic agents have been incorporated into the armamentarium for organ transplant recipients and patients with autoimmune diseases. Among the new drugs, mycophenolate mofetil (MMF) has acquired special relevance.1 In addition, MMF has also been added to the treatment of autoimmune diseases such as lupus, because its use has been found to be more effective than cyclophosphamide, the standard treatment modality, in inducing remission of lupus nephritis and has a more favorable safety profile.2 MMF is a newly available ester derived from mycophenolic acid. After oral ingestion, MMF is hydrolyzed rapidly to mycophenolic acid, the active compound (a potent noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase), which leads to depletion of intracellular guanosine triphosphate and 2 -deoxyguanosine 5 -triphosphate pools. This, in turn, blocks the de novo guanosine synthesis of precursors for RNA/DNA synthesis.3 Regarding the use of MMF in pregnancy, a specific pattern of fetal malformation has been attributed to MMF in experimental animals.4 Rat offspring whose mothers had been exposed to MMF exhibited anophthalmia, agnathia, hydrocephaly, and fetal resorptions. In rabbits exposed in utero, malformations included cardiovascular and renal abnormalities.5 Therefore, the information provided by MMF manufacturers underscores the relative risk of teratogenicity in animal models and includes a warning indicating that MMF has been upgraded in its classification as a pregnancy category D medication.6 It is important to note that in the last decade malformations described in human fetuses exposed to MMF were found to be similar to those documented in the experimental setting. However, it has not been until recently that a characteristic pattern has been identified and associated with the intake of MMF during pregnancy5 (Table 1). In an extensive review of the literature including Medline (PubMed), Embase, and the journal Reactions (ISNN 0114–9954), which specifically addresses information about adverse drug effects, we detected 10 cases of newborn infants with malformations associated with the intake of MMF during early stages of gestation (for references, see Table 1). Treatment with MMF was initiated in 7 cases after renal transplantation and in 3 cases for treatment of corticoid-resistant lupus glomerulonephritis. However, medication was immediately interrupted as soon as pregnancy was diagnosed between 8 and 10 weeks’ gestation. In 2 cases (3 and 10), the gestations were voluntarily interrupted in the 22nd and 17th weeks, respectively, but in most cases preterm infants were delivered; only 2 case pregnancies reached term. Fetal malformations were detected by routine prenatal sonogram and were not specifically sought by the obstetrician. Considering the different malformations described in the various clinical reports, a specific and consistent pattern of malformation was present in all of them. Hence, this phenotype includes craniofacial malformations affecting the oral cavity (thick everted lower lip, cleft lip and cleft palate) and ears (microtia and aural atresia) and ocular anomalies (hypertelorism, arching eyebrows). In addition, less-consistent findings have been limb abnormalities (hypoplastic finger and toe nails, bilateral shortened fifth finger, polydactyly) and congenital cardiovascular, renal, or central nervous system malformations. Developmental delay, however, has been an inconsistent finding that has not been specifically studied in most of the cases described in the literature. Thus, Perez-Aytes et al5 described their patient at 9 months of age as having had a normal structured neurologic evaluation and Bayley Developmental Index scores. In addition, Pérgola et al7 and Sifontis et al8 described both of theirs patients as having normal psychomotor development. However, the patient reported by Velinov and Zellers9 exhibited at 20 months of age an overall motor development delay and had a significant expressive speech delay. The above-described pattern establishes a link between exposure to MMF and development of the structures derived from the frontonasal prominence and first pharyngeal arch.5 The pattern is distinctive and unique

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.

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.

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.

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