A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

Abstract

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

Figure 1

Pharmacokinetics of very prolonged PEGasparaginase and Erwinia asparaginase use. (A) Serum PEGasparaginase activity levels (mean ± SEM) of children with or without allergy to or silent inactivation of PEGasparaginase (2500 IU/m² every other week) (n = 62). (B) Serum Erwinia asparaginase activity levels (mean ± SEM) of children without allergy to Erwinia asparaginase (20 000 IU/m² 2-3 times per week) (n = 57). In panel B, 3 curves are shown in the first 2 weeks of Erwinia asparaginase therapy. The upper curve (white open circles) shows 19 children who had high Erwinia asparaginase levels (72-hour levels ≥100 U/L) and were switched to infusions 2 times per week after the first 2 weeks of Erwinia asparaginase therapy. The lower curve (gray blocks) shows 38 children who had low Erwinia asparaginase levels (72-hour levels <100 U/L) and continued infusions 3 times per week after the first 2 weeks of Erwinia asparaginase therapy. The middle curve (closed circles) shows analysis of variance estimates of all 57 children receiving Erwinia asparaginase 3 times per week in the first 2 weeks.

Figure 2

Pharmacodynamics of very intensified PEGasparaginase courses. Serum asparagine (A), aspartic acid (B), glutamine (C), and glutamic acid (D) levels (mean ± SEM) during PEGasparaginase therapy (2500 IU/m²) in children without allergy to PEGasparaginase and without silent inactivation. Dashed lines show normal values of asparagine (40-80 μM), aspartic acid (4-22 μM), glutamine (457-738 μM), and glutamic acid (18-65 μM). The LLQ of asparagine is 0.2 μM.

Figure 3

Patients with AAAs during the consolidation phase and in the first two weeks of the intensification. Serum AAAs against native E coli asparaginase (Coli-AAA levels) of patients at day 79 (start of the consolidation phase) and at day 140 (start of the intensification) (A), and Coli-AAA levels and serum AAAs against PEGasparaginase (PEG-AAA levels) at day 140 (before first PEGasparaginase dose) and at day 154 (14 days after first PEGasparaginase dose) (B-C). Dashed lines indicate that samples were defined as positive for AAAs if the Coli-AAA OD was >0.13 and if the PEG-AAA OD was >0.25. Closed circles and blocks show cases with allergy or cases without allergy and without silent inactivation; silent inactivation cases are shown by open circles and blocks. Median Coli-AAA and PEG-AAA levels are indicated by bars. NS, not significant.

Figure 4

Pharmacodynamics of very intensified Erwinia asparaginase courses. Serum asparagine (A), aspartic acid (B), glutamine (C), and glutamic acid (D) levels (mean ± SEM) during Erwinia asparaginase therapy (20 000 IU/m²) in children without allergy to Erwinia asparaginase and without silent inactivation. Dashed lines show normal values of asparagine (40-80 μM), aspartic acid (4-22 μM), glutamine (457-738 μM), and glutamic acid (18-65 μM). The LLQ of asparagine is 0.2 μM.

Figure 5

Pharmacokinetics of very prolonged Erwinia asparaginase use in relation to AAAs. Serum Erwinia asparaginase activity (A) and serum AAAs (B) against Erwinia asparaginase (Erwinia-AAAs) over time. Serum Erwinia asparaginase activity levels of patients without Erwinia-AAAs (C) and with Erwinia-AAAs (D) (mean ± SEM). Dashed lines in panels A, C, and D indicate Erwinia asparaginase activity level of 100 U/L. The dashed line in panel B indicates samples defined as positive for Erwinia-AAAs if the OD was >1.96 standard deviations above the negative control processed mean (using Westgard rules).