A Pediatric Laboratory Experience: Measurement of L-Asparaginase Activity in Patients with Acute Lymphoblastic Leukemia. a Multicentric Study

INTRODUCTION

L-Asparaginase (L-Ase) is an essential component of multiagent chemotherapy for the treatment of childhood Acute Lymphoblastic Leukemia (ALL). Asparaginase achieves its antileukemic effect by depleting circulating asparagine and depriving cancer cells of this amino acid. Sufficient and sustained levels of asparagine depletion are important to obtaining optimal leukemic-cell death and favourable outcome. Patients are currently treated according to ALLIC-BFM GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) 2022 protocol. Pegylated L-Ase (PEG-L-Ase) is now primarily used as first-line treatment and Erwinia-L-Ase (asparaginase derived from the bacterium E. chrysanthemi) as a second line. Only two commercial brands are available in Argentina: PEG-L-Ase (Oncaspar^®, European) and Erwinia-L-Ase (Von Gott^®, Chinese). A minimal L-Ase activity level of 100 U/L is required for complete asparagine depletion. L-Ase activity levels show large intra and interpatient variability. For this reason, therapeutic drug monitoring (TDM) is essential for patients with ALL and is critical to detect silent inactivation (SI) of the drug due to anti-asparaginase neutralizing antibodies and perform a pharmacokinetic profile.

AIMS

The present study was designed to retrospectively evaluate the outcomes of TDM in children with ALL treated with asparaginase in 6 different hospitals from Argentina.

METHODS

This was a descriptive study that evaluates the results obtained from the measurement of L-Ase activity in serum samples from patients (1-18 years) with ALL from December 2018 to July 2024. Patients were treated according ALLIC-BFM GATLA 2010 or 2022 protocol. Relapses were treated with ALLIC-GATLA 2017 Relapse Protocol. Enzymatic activity was measured using the L-aspartic β-hydroxamate (AHA) assay. PEG-L-Ase monitoring was performed on days +7 and +14 and Erwinia-L-Ase 48 hours (h) after second and fifth dose. SI was defined as values <100 U/L on day +7 or <5 U/L on day +14 for the PEG-L-Ase, or with < 100 U/L at 48 h post-dose for the Erwinia-L-Ase.

RESULTS

A total of 849 serum (L-Ase) activities measurements were performed in a total of 279 patients. Of these, 796 samples (93.8%) were PEG-L-Ase and 53 (6.2%) were Erwinia-L-Ase. Of the 243 patients treated with PEG-L-Ase, 12 (4.9%) were diagnosed with SI and received treatment with Erwinia-L-Ase, obtaining L-Ase in therapeutic range in all of them. 24 patients who were treated with PEG-L-Ase presented inactivation with clinical manifestations such as rash and abdominal pain and had to be switched to Erwinia-LAse treatment. 61% of patients who presented PEG L-Ase inactivation were patients with relapsed ALL. 4 patients treated with Erwinia-L-Ase had L-Ase activity less than 100 U/L, 2 of them without clinical manifestations (SI).

CONCLUSIONS

These results support the importance of implementing TDM in the routine treatment of Acute Lymphoblastic Leukemia by strengthening the fact that it is the only evidence-based method currently available to identify silent inactivation and modificate the treatment, preventing potential therapeutics failures. Given that in Argentina only three centres perform L-Ase TDM, it is important to train and facilitate access to inputs in different parts of the country to increase TDM. In the future, it is planned to evaluate the outcome of patients and relate it to the activity measure.