<p>We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (<a href="http://clinicaltrials.gov/show/NCT00005585">http://clinicaltrials.gov/show/NCT00005585</a> and <a href="http://clinicaltrials.gov/show/NCT00005596)">http://clinicaltrials.gov/show/NCT00005596</a>). Patients received either a 24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose). Methotrexate clearance was lower in older children (p=7 x 10-7), females (p=2.7 x 10-4), and patients who received a delayed intensification phase (p=0.0022). In a genome-wide analysis, methotrexate clearance was associated with polymorphisms in the SLCO1B1 gene (p=2.1 x 10-11), which encodes for an organic anion transporter. This replicates findings using different schedules of high-dose methotrexate in ALL patients treated on St. Jude 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 (Trevino et al, PMID 19901119 and Ramsey et al, PMID 23233662). This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays.</p>

Methotrexate Clearance GWAS

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.

Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects.

Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition.

Genome-wide study of methotrexate clearance replicates SLCO1B1.