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.

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma

“…Guidelines have previously been published describing how to properly utilize asparaginase activity levels in children with ALL . Cooper et al showed that in newly diagnosed children with ALL, the use of premedicaton in conjunction with therapeutic drug monitoring reduced the rate of reactions and successfully identified silent inactivation . SAAs were available for most patients one week (6‐8 days) after the administration of pegaspargase utilizing a desensitization protocol with a mean of 0.66 ± 0.26 IU/mL ( n = 8).…”

“…These SAAs are comparable with published levels seven days after treatment with i.v. pegaspargase without a history of hypersensitivity, ranging from 0.6 to 0.9 IU/mL …”

“…21,22 Cooper et al showed that in newly diagnosed children with ALL, the use of premedicaton in conjunction with therapeutic drug monitoring reduced the rate of reactions and successfully identified silent inactivation. 23 SAAs were available for most patients one week (6-8 days) after the administration of pegaspargase utilizing a desensitization protocol with a mean of 0.66 ± 0.26 IU/mL (n = 8). These SAAs are comparable with published levels seven days after treatment with i.v.…”

“…pegaspargase without a history of hypersensitivity, ranging from 0.6 to 0.9 IU/mL. 23,24 We describe the use of a pegaspargase desensitization protocol in nine patients with a prior grade 3 or higher hypersensitivity reaction.…”

Increasing completion of asparaginase treatment in childhood acute lymphoblastic leukaemia (ALL): summary of an expert panel discussion

“…Also, a substantial financial saving was achieved. 21 Importantly, this strategy requires as an indispensable prerequisite to have a tight real-time TDM in place for each PEG asparaginase dose administered to detect silent inactivation. 4…”