title: Impact of SLCO1B1 521T > C variant on leucovorin rescue and risk of relapse in childhood acute lymphoblastic leukemia treated with high-dose methotrexate.
abstract: BACKGROUND
  Recent studies suggest that SLCO1B1 c.521T > C variant decreases the clearance of methotrexate (MTX) and elevates its plasma concentration, hence leucovorin doses may need to be adjusted. However, high leucovorin doses may affect the cure rate in childhood acute lymphoblastic leukemia (ALL). Hitherto neither the appropriate dose of leucovorin in carriers of SLCO1B1 c.521T > C variant nor the impact of SLCO1B1 polymorphism on the risk of ALL relapse has been clarified.
  
  
  METHODS
  A double-blind and controlled study was conducted in 136 children with ALL. They were genotyped for rs4149056 single nucleotide polymorphism into wild-type group and variant group, and received MTX at 3-5 g/m(2) . Plasma concentration MTX and its metabolite were determined by HPLC. The toxicity of MTX, dose of leucovorin and 5-year relapse rate of ALL were recorded.
  
  
  RESULTS
  Compared with wild-type group, area under the concentration time curve of MTX increased by 4.2-fold and peripheral clearance rate decreased significantly in variant group. Patients carrying rs4149056 C allele endured a remarkable longer time above the MTX safety threshold and suffered from a higher frequency of toxicity, so 2.2-fold leucovorin was given. However, no association was found between SLCO1B1 c.521T > C variant and the relapse risk in five years.
  
  
  CONCLUSIONS
  The SLCO1B1 c.521T > C variant was an important determinant of MTX disposition and their carriers were exposed to increased intensity and time of MTX. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity. The c.521T > C variant wasn't associated with the risk of ALL relapse.
authors.affiliation: Department of Clinical Pharmacology, Wuhan Children's Hospital, Hubei, China.
authors.forename: Hua-Nian
authors.initials: HN
authors.lastname: Zhang
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: He
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Li
authors.forename: Chang-He
authors.initials: CH
authors.lastname: Niu
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000209:etiology*; D009367:Neoplasm Staging; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D002955:Leucovorin; D008727:Methotrexate
keywords: SLCO1B1 polymorphism; acute lymphoblastic leukemia; leucovorin rescue; methotrexate; relapse; toxicity