Universal premedication and therapeutic drug monitoring for asparaginase-based therapy prevents infusion-associated acute adverse events and drug substitutions

Abstract

Background: Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions.

Procedure: Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost.

Results: We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient).

Conclusions: Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.

Keywords: asparaginase; leukemia; premedication; therapeutic drug monitoring.

FIGURE 1

Premedication reduces the risk of drug substitution and the rate of clinical reactions. The rate of substitution from PEG to ERW (left) and rate of clinically significant reactions (right) were compared between patients treated pre-policy and post-policy. Significance was tested by bootstrap resampling using 1 × 106 resamplings. Error bars are standard errors of the average

FIGURE 2

Premedication reduces the severity of clinically apparent reactions. Clinically significant reactions were graded according to CTCAE 4.03. Graphed are the percentages of all patients treated with PEG pre-policy and post-policy who experienced each grade of reaction. Rates are charted according to each organ system examined and for all organ systems in aggregate. No grade 5 reactions were experienced during the study period. No grade 4 reactions were experienced after implementation of the premedication policy

FIGURE 3

TDM of asparaginase-based therapy. SAA testing was performed for post-policy patients one week after PEG administration or two to three days after ERW administration. A, Comparison of SAA levels for all completed doses of PEG with ERW doses. B, Comparison of SAA levels following PEG achieved by patients who completed therapy without drug substitution (“Never reacting”) with levels achieved by patients who would ultimately be substituted to ERW for all PEG doses prior to the final, offending dose (“Pre-reacting doses”). C, Comparison of SAA levels following ERW administration achieved by patients without evidence of prior PEG inactivation with those with negative PEG SAA testing