Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug‐supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

August

Farooki

Fulbright

et al. 2019

“…Additionally, it is now available as a CLIA‐certified test with a turnaround time of less than one week, allowing real‐time decision‐making and therapeutic adjustments. Generally accepted SAA assay targets include a minimum trough of ≥ 0.1 IU/mL . However, data indicate that sustained asparagine depletion is critical for improved outcomes .…”

Section: Introductionmentioning

confidence: 99%

“…Generally accepted SAA assay targets include a minimum trough of ≥ 0.1 IU/mL. 25 However, data indicate that sustained asparagine depletion is critical for improved outcomes. 5,26 Furthermore, pharmacokinetic studies indicate that when SAA levels fall below 0.4 IU/mL, asparagine is no longer completely depleted, and begins to rebound, indicating an optimal trough ≥ 0.4 IU/mL.…”

Section: Introductionmentioning

confidence: 99%

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

Cooper¹,

Young²,

Bowen³

et al. 2019

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.

“…or i.m. MWF (6 Erwinase doses = 1 PEG‐ASP dose) 15 and the global shortage of Erwinase limits our ability to give higher doses, our data suggest that doses higher than 25 000 IU/m 2 for Erwinase are required to maintain asparaginase activity > 0.1 in over 80% of patients.…”

Section: Discussionmentioning

confidence: 92%

Higher plasma asparaginase activity after intramuscular than intravenous Erwinia asparaginase

Panetta

Liu

Swanson

et al. 2020

It is unclear if dosing intervals for Erwinase can be extended with intramuscular (i.m.) versus intravenous (i.v.) dosing. Children with acute lymphoblastic leukemia received Erwinase at 30 000-42 000 IU/m 2 i.v. or i.m. I.m. Erwinase (n = 22) achieved activity above 0.1 IU/mL for longer than i.v. Erwinase (n = 33) (3.4 vs 2.9 days, P = 0.0007). With 30 000 IU/m 2 Monday, Wednesday, Friday, more patients achieved adequate concentrations over the weekend with i.m. vs i.v. dosing (P = 5 × 10 −36 ). A schedule with i.v. doses on Monday and Wednesday and i.m. doses on Friday of 30 000 IU/m 2 maintained activity > 0.1 IU/mL over the weekend in 80% of patients. K E Y W O R D S acute lymphoblastic leukemia, asparaginase, Erwinase, intramuscular, intravenous, pharmacokinetics