Individualized therapeutic drug monitoring of asparaginase may maintain sufficient asparaginase depletion and reduce the necessary dosage among pediatric patients with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology. Therapeutic drug monitoring does not, however, appear to meaningfully reduce toxicity.

Asparaginase, an essential part of effective treatment for pediatric patients with acute ALL, starves cancer cells through extracellular asparaginase depletion. However, the enzyme’s activity must be greater than 100 IU/L for sufficient depletion.

In addition, patients can have hypersensitive reactions, with or without clinical symptoms, to asparaginase treatment. In the absence of symptoms, patients must be taken off polyethylene glycol-conjugated Escherichia coli asparaginase (PEG-asparaginase) and receive Erwinia asparaginase instead. There are other treatment-associated toxicities as well that may lead to worse clinical outcomes.

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For this study, researchers implemented therapeutic drug monitoring in the Dutch Childhood Oncology Group (DCOG) ALL-11 treatment protocol to determine whether adjusted asparaginase dosage helps reduce toxicity while maintaining sufficient asparaginase depletion.


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Overall, 382 patients were included, and the median age was 5.3 years. All patients received 3 fixed intravenous induction doses of 1500 IU/m2 PEG-asparaginase. After induction therapy, patients were grouped by risk into 3 cohorts: standard risk (108 patients), medium risk (243 patients), and high risk (18 patients). Thirteen patients received only induction therapy because of experiencing toxicity or relapse.

Patients with standard risk received 1 individualized dose. Patients with medium risk received 14 individualized doses targeting trough levels of 100 U/L to 250 IU/L. Patients with high risk received 2 to 5 fixed administrations of 1500 IU/m2 PEG-asparaginase. Patients with a neutralizing hypersensitivity event were switched to 20,000 IU/m2 Erwinia asparaginase 3 times per week.

At analysis, the median PEG-asparaginase dose was 450 IU/m2, and 97% of trough levels in nonallergic patients were greater than 100 IU/L; 10% of patients, however, developed hypersensitivity, and 40% of these patients showed no clinical symptoms. The frequencies of grade 3 to 4 pancreatitis, thrombosis, and central neurotoxicity were, respectively, 12%, 6%, and 4% overall. Medium-risk patients demonstrated grade 3 to 4 increased alanine aminotransferase, hyperbilirubinemia, and hypertriglyceridemia rates of 50%, 3%, and 37%, respectively.

“Therapeutic drug monitoring of asparaginase is feasible in a nationwide program and results in a substantial dose reduction without loss of efficacy of treatment, as reflected by asparagine depletion, although survival analyses should be awaited,” the researchers concluded. “However, the effect of the PEG-asparaginase dose reduction on asparaginase-associated toxicities is limited.”

Reference

1.     Kloos RQH, Pieters R, Jumelet FMV, de Groot-Kruseman HA, van den Bos C, van der Sluis IM. Individualized asparaginase dosing in childhood acute lymphoblastic leukemia [published online January 10, 2020]. J Clin Oncol. doi:10.1200/JCO.19.02292