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Genome-wide study of methotrexate clearance replicates SLCO1B1.

Publication ,  Journal Article
Ramsey, LB; Panetta, JC; Smith, C; Yang, W; Fan, Y; Winick, NJ; Martin, PL; Cheng, C; Devidas, M; Pui, C-H; Evans, WE; Hunger, SP; Loh, M; Relling, MV
Published in: Blood
February 7, 2013

Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children’s Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 x 10(-7)), girls (P = 2.7 x 10(-4)), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 x 10(-11)). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 x 10(-19) for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 7, 2013

Volume

121

Issue

6

Start / End Page

898 / 904

Location

United States

Related Subject Headings

  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Organic Anion Transporters
  • Multivariate Analysis
  • Methotrexate
  • Metabolic Clearance Rate
  • Male
  • Liver-Specific Organic Anion Transporter 1
  • Linear Models
  • Leucovorin
 

Citation

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Ramsey, L. B., Panetta, J. C., Smith, C., Yang, W., Fan, Y., Winick, N. J., … Relling, M. V. (2013). Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood, 121(6), 898–904. https://doi.org/10.1182/blood-2012-08-452839
Ramsey, Laura B., John C. Panetta, Colton Smith, Wenjian Yang, Yiping Fan, Naomi J. Winick, Paul L. Martin, et al. “Genome-wide study of methotrexate clearance replicates SLCO1B1.Blood 121, no. 6 (February 7, 2013): 898–904. https://doi.org/10.1182/blood-2012-08-452839.
Ramsey LB, Panetta JC, Smith C, Yang W, Fan Y, Winick NJ, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013 Feb 7;121(6):898–904.
Ramsey, Laura B., et al. “Genome-wide study of methotrexate clearance replicates SLCO1B1.Blood, vol. 121, no. 6, Feb. 2013, pp. 898–904. Pubmed, doi:10.1182/blood-2012-08-452839.
Ramsey LB, Panetta JC, Smith C, Yang W, Fan Y, Winick NJ, Martin PL, Cheng C, Devidas M, Pui C-H, Evans WE, Hunger SP, Loh M, Relling MV. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013 Feb 7;121(6):898–904.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 7, 2013

Volume

121

Issue

6

Start / End Page

898 / 904

Location

United States

Related Subject Headings

  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Organic Anion Transporters
  • Multivariate Analysis
  • Methotrexate
  • Metabolic Clearance Rate
  • Male
  • Liver-Specific Organic Anion Transporter 1
  • Linear Models
  • Leucovorin