Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase

Abstract

Purpose: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL).

Methods: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m² IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m² or 3500 IU/m² IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM.

Results: During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3).

Conclusions: The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.

Keywords: Acute lymphoblastic leukemia; Asparagine; Cerebrospinal fluid; Erwinia asparaginase; Pediatric; Pegylated asparaginase; Pharmacodynamics; Pharmacokinetics.

Figure 1:

CSF asparagine Visual Predictive Check. Black dots: measured CSF asparagine concentration. Red dots: measured CSF asparagine below the LLOQ. These values were plotted at the LLOQ. Solid black curve and blue shaded region: population simulated median and 95% confidence interval. Dashed black curves and grey shaded regions: population simulated 10^th and 90^th percentiles and 95% confidence intervals. Green solid and dotted curves: individual estimated median, 10^th and 90^th percentiles. Yellow dashed curve: median estimated serum asparaginase activity; yellow shaded regions 25^th-75^th and 5^th-95^th percentiles estimated serum asparaginase activity. A: Induction 3,000 IU/m² on day 3; B: Induction 3,000 IU/m² on day 3 and day 15; C: Reinduction I Low Risk (LR), 2,500 IU/m² pegaspargase; D: Reinduction I LR, 3,500 IU/m² pegaspargase; E: Continuation Week 1 to end of Reinduction I Std/High Risk (SHR), 2,500 IU/m² pegaspargase; F: Continuation Week 1 to end of Reinduction I (SHR), 3,500 IU/m² pegaspargase.

Figure 2:

Induction Time below CSF asparagine Threshold. Estimated time CSF asparagine was depleted below 1 μM given a dose of 3,000 IU/m² pegaspargase in those who received only day 3 pegaspargase (n=331) vs those who received day 3 and day 15 pegaspargase (n=151) during Induction. Shown as medians: horizontal bar; 25^th-75^th quartiles: box; and, non-outlier range (1.5 times the quartile range): whiskers.

Figure 3:

Time below CSF asparagine threshold subdivided by formulation and route given the following hypothetical doses and schedules. Simulated time CSF asparagine was depleted below 1 μM given either 10 erwinase doses every 3 days (either 30,000 or 42,000 IU/m² and either IV or IM) or 2 pegaspargase IV doses Q14D (either 2,500 or 3,500 IU/m²). A.) Low Risk. B.) Standard/High Risk. Shown as medians: horizontal bar; 25^th-75^th quartiles: box; and, non-outlier range (1.5 times the quartile range): whiskers.

Figure 4:

Population Estimated CSF asparagine and serum asparaginase activity vs time given the following hypothetical doses and schedules. Simulated CSF asparagine activity based on 10 erwinase doses every 3 days. Black curve: median estimated CSF asparagine; Green dashed curve: median estimated serum asparaginase activity; shaded regions 25^th-75^th and 5^th-95^th percentiles. A: 30,000 IU/m² IV erwinase, LR; B: 30,000 IU/m² IM erwinase, LR; C: 30,000 IU/m² IV erwinase, SHR; D: 30,000 IU/m² IM erwinase, SHR; E: 42,000 IU/m² IV erwinase, LR; F: 42,000 IU/m² IM erwinase, LR; G: 42,000 IU/m² IV erwinase, SHR; H: 42,000 IU/m² IM erwinase, SHR.