Methotrexate Clearance GWAS

We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (http://clinicaltrials.gov/show/NCT00005585 and http://clinicaltrials.gov/show/NCT00005596). 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.]]>
Confirmed diagnosis of newly diagnosed B-precursor acute lymphocytic leukemia Participant is less than or equal to 21 years of age Written, informed consent following NCI, IRB, FDA, and OPRR Guidelines Patient received high-dose methotrexate as part of protocol-directed therapy for ALL ]]>
Patients treated on two clinical trials are included here: Children Oncology Group multi-institutional trials P9904 and P9905. Patients were randomized in a 2x2 manner to one of four arms for consolidation: A, 24-hour methotrexate infusion (1 g/m2 given as a 200 mg/m2 bolus over 20 minutes, followed by 800 mg/m2 over 23.6 hours) and no delayed intensification (DI) phase; B, 4-hour methotrexate infusion (2 g/m2) with no DI; C, 24-hour methotrexate infusion with DI; D, 4-hour methotrexate infusion with DI. (Borowitz et. al, Blood. 2008 Jun 15;111(12):5477-85.; Ramsey et al Blood. 2013 Feb 7;121(6):898-904.) P9904 first patient enrolled: April 2000 P9904 last patient enrolled: April 2005 P9905 first patient enrolled: April 2000 P9905 last patient enrolled: April 2005]]>