Table 1.
Summary statistics of patients in this study.
Figure 1.
MTX and MTXPG concentration vs time plots.
(A) Plasma MTX concentration (µM) vs time (hrs). (B) Intracellular MTX (MTXPG1) concentration in peripheral blood cells (pmol/109 cells) vs time (hrs). (C) Intracellular MTXPG2-7 concentration in peripheral blood cells (pmol/109 cells) vs time (hrs). Black lines and circles represent the model fit and data given a 24 hour infusion and green lines and dimonds represent the model fit and data given a 4 hour infusion. We plotted the MTXPG concentrations at fixed time points around each sampling time to prevent the samples from the two different infusion groups from overlapping.
Table 2.
MTX and MTXPG model parameters.
Figure 2.
NET-influx (model parameter describing the net influx of MTX) vs ALL ploidy (hyperdiploid vs non-hyperdiploid). Median, quartiles, non-outliers range (defined as 1.5 times the interquartile range), and outliers (plus-marks) are depicted for B-lineage ALL.
Figure 3.
MTX metabolizing enzyme model parameters vs ALL subtype.
(A) VMAX FPGS vs molecular subtype. (B) NET-PG (net accumulation of MTXPG) vs molecular subtype. Median, quartiles, non-outliers range (defined as 1.5 times the interquartile range), and outliers (plus-marks) are depicted. The subtypes are defined as follows: BHD, B-lineage hyperdiploid ALL; BNHD, B-lineage non-hyperdiploid without the t(12;21) [ETV6-RUNX1] or t(1;19) [TCF3-PBX1] translocation; ETV6-RUNX1, B-lineage non-hyperdiploid with the t(12;21) [ETV6-RUNX1] translocation; TCF3-PBX1, B-lineage non-hyperdiploid with the t(1;19) [TCF3-PBX1] translocation; and T, T-lineage ALL.
Figure 4.
MTXPG model parameters vs gene expression in ALL blasts at diagnosis.
(A) SLC19A1 expression (Probe Set ID: 209775_x_at) vs Influx. (B) SLC19A1 (Probe Set ID: 211576_s_at) vs NET-influx. (C) FPGS expression (Probe Set ID: 202945_at) vs NET-PG.
Figure 5.
MTXPG model parameters vs germline SNPs.
(A) VMAXFPGS vs FPGS SNP (DB SNP ID: rs1544105). (B) VMAXFPGS vs FPGS SNP (DB SNP ID: rs7033913). The p-values were determined by the Kruskal-Wallis ANOVA.
Figure 6.
Individual simulated intracellular MTXPG and intracellular folate concentrations vs time.
Dose: 1 g/m2; Infusion time: 24 hrs. Red: DHF; Green: THF; Light Blue: 5,10-CH2-THF; Magenta: 5mTHF; Yellow: 5,10-CH = THF; Dark Blue: 10f-THF; Solid Black: MTXPG1; Dashed Black: MTXPG2-7.
Figure 7.
Simulations of the effects of lineage and dosage on model estimated DNPS activity.
The curves represent the median and the shaded regions represent the quartiles of the results from the respective simulated patient populations. (A) Simulated percent change in DNPS vs time after a 1 g/m2 dose of MTX. Solid curve and Red shading: B-lineage Hyperdiploid; Dashed curve and Blue shading: T-lineage. (B) Simulated percent change in DNPS at 42 hrs vs Dose. Solid curve and Red shading: 24 hr MTX infusion; Dashed curve and Blue shading: 4 hr MTX infusion.
Figure 8.
(A) The pharmacokinetic model for plasma and intracellular MTX and MTXPG [9]. The parameters are defined in the text. The dashed line describing the efflux of intracellular MTX back to the plasma represents the fact that the system is uncoupled, i.e. we account for the efflux of intracellular MTX but we do not explicitly account for its return to the plasma. (B) The folate pathway model [12] is modified to include the pathways inhibited by MTXPG. The model parameters (described by arrows) are defined in the text and supplemental material.