Downloaded from http://journals.lww.com/jpharmacogenetics by BhDMf5ePHKbH4TTImqenVBaqevB2sTM0B65m1HXBzZdmN8cLe1MH5loMe5UUUMS+ on 09/10/2018 Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia: a single institution study Nathalie K. Zgheib a , Khaled M. Ghanem b , Hani Tamim c , Carole Aridi b , Randa Shahine b , Nidale Tarek b , Raya Saab b , Miguel R. Abboud b , Hassan El-Solh b and Samar A. Muwakkit b Objective The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL). Patients and methods This is a retrospective evaluation of 133 Arab children treated for ALL at the Children’s Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Genotyping for ABCB1 (rs1045642), ABCB1 (rs1128503), ABCC2 (rs717620), CEP72 (rs924607), ETAA1 (rs17032980), and MTNR1B (rs12786200) was performed. Results A total of 26 (19.5%) individuals developed peripheral neuropathy, three of which occurred during the induction phase. No statistically significant associations were revealed for any of the polymorphisms with either incidence of vincristine-related toxicity, toxicity severity, or time to the first episode of grade 2 or higher vincristine- related peripheral neuropathy. Conclusion This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mg/m 2 ) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world. Pharmacogenetics and Genomics 28:189–195 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Pharmacogenetics and Genomics 2018, 28:189–195 Keywords: acute lymphoblastic leukemia, genetic polymorphisms, neuropathy, vincristine Departments of a Pharmacology and Toxicology, b Pediatrics and Adolescent Medicine and c Internal Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon Correspondence to Samar A. Muwakkit, MD, Department of Pediatrics and Adolescent Medicine, Children’s Cancer Center of Lebanon, PO Box 113-5067, Clemenceau Street, Beirut, Lebanon Tel: + 961 1 350 000; fax: + 961 1 360 496; e-mail: sm03@aub.edu.lb Received 9 April 2018 Accepted 27 July 2018 Introduction The introduction of novel therapeutic approaches and dedicated treatment protocols for children with acute lymphoblastic leukemia (ALL) surely translated into improved outcomes, such as survival rates exceeding 90% in most developed countries [1]. However, there remain continuous efforts to optimize safety of treatment because, although the doses for antileukemic agents are calculated according to standardized protocols, prediction of toxicity is still difficult owing to wide interindividual variability. Based on this, investigators have been extensively assessing associations between candidate gene polymorphisms and ALL treatment toxicity and outcome. The focus has been on the commonly used drugs with the most compelling evidence being for 6-mercaptopurine therapy and risk of myelosuppression [2–4]. We have recently used the candidate gene approach and shown clinically significant results with methotrexate and 6-mercaptopurine-related myelotoxi- city [5,6]; nevertheless, we noticed additional adverse events that are worth pursuing. These include somatic, sensory, and motor peripheral neuropathies that are peculiar and dose limiting to vincristine therapy [7]. As a matter of fact, the vinca alkaloids’ pharmacokinetics were previously shown to be associated with a large inter- individual variability [8,9]. In addition, Renbarger et al. [10] have reported significant differences in neuropathy Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.pharmacogeneticsandgenomics.com. Original article 189 1744-6872 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FPC.0000000000000345 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.