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Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia
Robin Q H Kloos1, Rob Pieters2, Florine M V Jumelet1
1Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
Insights
Therapeutic drug monitoring (TDM) for asparaginase in pediatric acute lymphoblastic leukemia reduces PEGasparaginase dosage while maintaining efficacy. TDM helps identify silent inactivation but has limited impact on asparaginase-associated toxicities.
Area of Science:
- Oncology
- Pharmacology
Background:
- Pediatric acute lymphoblastic leukemia (ALL) treatment often involves asparaginase, an enzyme that depletes asparagine.
- Asparaginase therapy can be associated with toxicities and variable efficacy.
- Individualizing asparaginase dosing through therapeutic drug monitoring (TDM) may optimize treatment outcomes.
Purpose of the Study:
- To evaluate the efficacy of therapeutic drug monitoring (TDM) for individualized asparaginase dosing in pediatric ALL.
- To assess the impact of TDM on asparaginase-associated toxicities within the DCOG ALL-11 protocol.
Main Methods:
- The DCOG ALL-11 protocol utilized polyethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase.
- Patients received individualized PEGasparaginase doses targeting specific trough levels (100-250 IU/L) based on risk stratification.
- Asparagine levels were monitored to assess asparaginase efficacy, and various asparaginase-associated toxicities were studied.
Main Results:
- TDM led to a significant reduction in the median PEGasparaginase dose to 450 IU/m² while achieving adequate trough levels (>100 IU/L) in 97% of patients.
- Asparagine depletion was achieved in 96% and 67% of PEGasparaginase and Erwinia asparaginase treatments, respectively.
- While TDM identified silent inactivation (40% of hypersensitivity reactions), its effect on reducing grade 3-4 pancreatitis, neurotoxicity, and thromboses was limited. Grade 3-4 ALT elevations and hypertriglyceridemia were observed during treatment.
Conclusions:
- TDM of asparaginase effectively reduces PEGasparaginase dosage and ensures adequate enzyme activity and asparagine depletion in pediatric ALL.
- TDM is valuable for detecting silent inactivation and allergic-like reactions to asparaginase.
- The impact of TDM-guided dose reduction on overall asparaginase-associated toxicity remains limited.
Purpose:
In the DCOG ALL-11 protocol, polyethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia 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.
Patients And Methods:
After induction with 3 fixed intravenous doses of 1,500 IU/m2 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/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied.
Results:
The final median PEGasparaginase dose was lowered to 450 IU/m2. 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 Erwinia 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% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification.
Conclusion:
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.
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