Hematologic toxicity and MTX levels according to MRP4 genotypes. (A) Relationship between MRP polymorphisms and frequency of high-grade thrombocytopenia. The presence (■) and absence (□) of at least one episode of thrombocytopenia grade 3 and/or 4 in persons with different MRP genotype groups (top panel) or genotypes of CA934 polymorphism (bottom panel). P values for the difference between genotypes are obtained by χ² (p1) and by Kruskal-Wallis or Mann-Whitney test (p2) for the difference in toxicity rates. Toxicity was graded using the common criteria for adverse events of the National Cancer Institute.²⁰  The mean number of weeks assessed per patient was 80. (B) Relationship between MRP polymorphisms and retention of MTX in plasma at concentration higher than 1 μM. Concentration more than 1 μM 72 hours after high-dose MTX are indicated by ■, and concentrations less than or equal to 1 μM are indicated by □ in persons with different MRP genotype groups (top panel) or genotypes of TC-1393 polymorphism (bottom panel). MTX plasma levels were measured by fluorescence polarization immunoassay (TDx; Abbott Laboratories) following the manufacturer's instructions. P value for the difference between genotypes is obtained by χ². (C) Relationship between MRP polymorphisms and MTX plasma levels. Lines represent log values of MTX levels (μM, measured at 2 time points after high-dose MTX) in persons with different MRP genotype (top panel) or genotypes of TC-1393 polymorphism (bottom panel). P values are obtained by repeated measures analysis of variance. In panels A and B, genotypes are indicated on the x-axis. The number of persons represented by white and black bars is indicated above and below each plot, respectively. In panel C, genotype groups, genotypes, and number of persons represented by each line are indicated on the plots. Given that the data on toxicity were available for 174 patients only, we analyzed an association between MRP4 polymorphisms and EFS in this subgroup. The same trend was observed (P = .1 for TC-1393 and AC934 genotype, and P = .02 for genotype groups).