Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia

In the DCOG ALL-11 protocol, polyethylene glycol-conjugated asparaginase (PEGasparaginase) and asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are report...

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Bibliographic Details
Published in:	Journal of clinical oncology Vol. 38; no. 7; pp. 715 - 724
Main Authors:	Kloos, Robin Q H, Pieters, Rob, Jumelet, Florine M V, de Groot-Kruseman, Hester A, van den Bos, Cor, van der Sluis, Inge M
Format:	Journal Article
Language:	English
Published:	United States 01-03-2020
Subjects:	Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Asparaginase - administration & dosage Asparaginase - adverse effects Child Child, Preschool Dose-Response Relationship, Drug Drug Hypersensitivity - etiology Humans Polyethylene Glycols - administration & dosage Polyethylene Glycols - adverse effects Precision Medicine Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Randomized Controlled Trials as Topic
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Summary:	In the DCOG ALL-11 protocol, polyethylene glycol-conjugated asparaginase (PEGasparaginase) and asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. After induction with 3 fixed intravenous doses of 1,500 IU/m PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m ). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. The final median PEGasparaginase dose was lowered to 450 IU/m . Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/jco.19.02292