Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children's Oncology Group AALL07P4

Abstract

The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of plasma asparaginase activity to achieve asparagine depletion has been between 0.05 and 0.4 IU/mL. COG AALL07P4 examined the asparaginase activity and plasma and CSF asparagine concentration of pegaspargase when given intravenously in the treatment of NCI high risk ALL. Matched plasma asparaginase/asparagine levels of the clearance of 54 doses of pegaspargase given in induction or consolidation demonstrated that all patients who had a plasma asparaginase level >0.02 IU/mL had undetectable plasma asparagine. No difference was observed in CSF asparagine levels associated with matched plasma asparaginase levels of 0.02-0.049 versus 0.05-0.22 IU/mL (p = .25). Our data suggest that a plasma asparaginase activity level of 0.02 IU/mL can effectively deplete plasma asparagine. The data also indicate that the 95% CI for plasma asparagine depletion after a pegaspargase dose is 22-29 days. Clinical trial registration: clinicaltrials.gov identifier NCT00671034.

Keywords: Lymphoid Leukemia; asparaginase; asparagine depletion; pharmacodynamics; pharmacokinetics.

Figure 1.. (A) 619 Asparaginase Levels after 86 Induction and Consolidation Doses of Pegaspargase, 2500 IU/m², in 48 Patients, and (B) 95% Confidence Intervals of 480 Values on Days 1–28.

Regressions are 2° polynomials were determined with 25 undetectable values (all during days 14–28) assumed to be zero (0). The horizontal, dashed line indicates when, according to the results of this study, asparagine is repleted after asparaginase declines below this level. The polynomial regression is virtually identical if undetectable levels were defined as 0.001 or 0.010 IU/mL

Figure 2.. The Two Patients with Asparagine Repletion at the Lowest Detectable Asparaginase Levels.

A. Induction dose in a patient whose plasma asparagine returned to pretreatment levels when the plasma asparaginase level was 0.014 IU/mL. B. Consolidation dose in a patient whose plasma asparagine returned to pretreatment levels when the plasma asparaginase level was 0.016 IU/mL.

Figure 3.. Three Patients with Complete Asparagine Depletion at Asparaginase Levels between 0.08 and 0.30 IU/mL.

The insets depict paired asparagine levels for each patient’s asparaginase levels shown in the primary graph. Patients C, D and E received 17%, 3% and 31%, respectively, of the planned 2,500 IU/m² dose due to hypersensitivity reactions.

Figure 4.. CSF Asparagine Concentration 15 to 43 Days after Pegaspargase, 2,500 IU/m² IV, as a Function of Plasma Asparaginase activity, Based on All Available Paired Samples.

Gray circles are 8 pairs with undetectable plasma asparaginase (<0.013 IU/mL). Solid black dots outlined by a black dashed line are 10 pairs with plasma asparaginase activity between 0.02 and 0.05 IU/mL and their linear regression are denoted in red. Open circles represent 22 pairs with plasma asparaginase activity >0.05 IU/mL.