A Genome-Wide Analysis of Variants Influencing Methotrexate Clearance Replicates SLCO1B1.
High-dose methotrexate (HDMTX) is an important element of chemotherapy for acute lymphoblastic leukemia (ALL) and other malignancies. Methotrexate clearance influences cure and toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX schedules and doses vary widely among treatment protocols. The Children's Oncology Group (COG) tested the efficacy of 6 courses of 2 g/m2 over 4 hours versus 1 g/m2 over 24 hours (P9904 and P9905 protocols). Patients were assigned to one of four arms for consolidation: A, 24-hour methotrexate infusion (1 g/m2) and no delayed intensification (DI); 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. We estimated methotrexate clearance for 1279 patients treated on these protocols, with two plasma MTX concentrations per course, using a Bayesian pharmacokinetic modeling approach. Germline genetic variation was assessed using the Affymetrix 6.0 array, and other single nucleotide polymorphisms (SNPs) were imputed based on 1000 Genomes reference data, yielding 5.2 million SNP genotypes evaluable per patient.
Average MTX clearance was highly variable, with a median (range) of 164 (65–355) and 109 (49–290) ml/min/m2 for the 24-hour and 4-hour infusions, respectively. Methotrexate clearance was lower in older children (p = 7 × 10−7), girls (p = 2.7 × 10−4), and patients who received a delayed intensification phase during consolidation (p = 0.0022). Adjusting for age, gender, race, and treatment arm, a genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in SLCO1B1(p = 2.1 × 10−11), a gene that encodes for an organic anion transporter that is known to transport methotrexate. This replicates our previous findings (Trevino et al, J Clin Oncol. 2009;27(35):5972-8) that polymorphisms in SLCO1B1 influence methotrexate clearance in ALL patients treated on St. Jude protocols with three different HDMTX schedules. In a combined meta-analysis including the 1279 COG patients and 699 St. Jude patients, and adjusting for age, gender, race, and treatment arm, the association of methotrexate clearance with SLCO1B1 SNP rs4149056 yields a p-value of 3.1 × 10−19 (Figure). Even after adjustment for the rs4149056 SNP, other polymorphisms in SLCO1B1 remained significantly related to methotrexate clearance, indicating that there are multiple variants in SLCO1B1 that can influence methotrexate clearance. Validation of the association of this gene with five different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance.
No relevant conflicts of interest to declare.
Ramsey, LB; Panetta, JC; Smith, C; Yang, W; Fan, Y; Winick, N; Martin, PL; Cheng, C; Devidas, M; Pui, C-H; Evans, WE; Hunger, SP; Loh, ML; Relling, MV
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