BACKGROUND: E.coli L-asparaginase (E.coli-ASP) is an important component of multiagent chemotherapy for childhood ALL, but is associated with multiple toxicities, including allergy in 25–30% of patients. Pegaspargase (PEG), the polyethylene glycol conjugate of E.coli ASP, has a longer circulating half-life and potentially decreased immunogenicity. All ASP preparations, including PEG, have generally been given intramuscularly (IM) in North America, although limited data suggests that PEG ASP may be safely given intravenously (IV).

METHODS: On DFCI ALL Consortium Protocol 05-01 (open since May 2005), all patients (pts) with newly diagnosed ALL (ages 1–18 years) receive a single dose of IV PEG (2500 units/m2) on Day 7 of a 32-day multiagent induction regimen. Serum ASP enzyme levels (measured by validated biochemical assay) are assayed 4, 11, 18 and 25 days after the PEG dose. Lower limit of quantitation of the assay is 0.025 IU/mL. ASP levels >=0.1 IU/mL have previously been correlated with asparagine depletion.

RESULTS: Between May 2005–April 2006, 66 eligible pts were enrolled and received a single dose of IV PEG during remission induction. Median age was 5 years (range 1–16 years), median WBC was 11.3K/microliter, 60% were male and 16% had T-cell phenotype. 58% were considered standard risk and 42% high risk. ASP-related toxicities occurred in 3 (4.5%) pts. Toxicities included hypersensitivity during PEG infusion (N=1), deep venous thrombosis (N=1, 24 days after PEG), and mild pancreatitis (N=1, 20 days after PEG). 1 patient died of Bacillus sepsis (14 days after PEG). Serum ASP enzyme levels were obtained in 62 patients (Table 1). There was no significant difference in serum ASP levels at any timepoint (using Wilcoxon Rank Sum Test) when comparing pts < 10 years old with those >=10 years old (Table 2), or when comparing male and female pts.

CONCLUSIONS: We conclude that IV administration of PEG is feasible and tolerable in children with ALL. Most pts have potentially therapeutic serum ASP levels (>=0.10 IU/mL) for up to 18 days after a single dose. Serum ASP levels after IV PEG are similar to those seen after IM administration. In order to determine toxicity, efficacy and pharmacodynamics of repeated doses of IV PEG, we are currently randomizing children with ALL to receive 30 weeks of either IV PEG (given every 2 weeks) or IM E.coli (given weekly) during post-induction consolidation.

Table 1:

Serum ASP levels after single dose IV PEG

Days After IV PEGNMinimum LevelMaximum LevelMedian Level%pts with level ≥ 0.10
Serum ASP levels in IU/mL 
4 45 <0.025 2.338 0.783 98% 
11 52 <0.025 1.396 0.457 94% 
18 40 0.041 0.478 0.203 80% 
25 52 <0.025 0.120 <0.025 2% 
Days After IV PEGNMinimum LevelMaximum LevelMedian Level%pts with level ≥ 0.10
Serum ASP levels in IU/mL 
4 45 <0.025 2.338 0.783 98% 
11 52 <0.025 1.396 0.457 94% 
18 40 0.041 0.478 0.203 80% 
25 52 <0.025 0.120 <0.025 2% 
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Table 2:

Serum ASP levels after IV PEG by patient age

Median Serum ASP levels (min, max)
Days After IV PEGAge < 10 yrsAge >=10 yrsp-value
Serum ASP levels in IU/mL 
4 0.79 (<0.025,2.34) 0.72 (0.39,1.63) 0.41 
11 0.49 (<0.025,1.01) 0.34 (<0.025,1.40) 0.28 
18 0.22 (0.04,0.48) 0.18 (0.05,0.40) 0.42 
25 <0.025 <0.025 0.11 
Median Serum ASP levels (min, max)
Days After IV PEGAge < 10 yrsAge >=10 yrsp-value
Serum ASP levels in IU/mL 
4 0.79 (<0.025,2.34) 0.72 (0.39,1.63) 0.41 
11 0.49 (<0.025,1.01) 0.34 (<0.025,1.40) 0.28 
18 0.22 (0.04,0.48) 0.18 (0.05,0.40) 0.42 
25 <0.025 <0.025 0.11 
View Large

Topics:
leukemia, lymphocytic, acute, childhood, pegaspargase, remission induction, brachial plexus neuritis, single-dose regimen, toxic effect, enzymes, hypersensitivity, asparaginase, asparagine

Disclosures: Dr. Sallan has acted as a consultant to Enzon (manafacturere of Oncospar).; Enzon has partially funded laboratory performing ASP enzyme level testing.; Drs. Sallan and Silverman have received honoraria for speaking engagements from Enzon.

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2006, The American Society of Hematology
2006
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