Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

Children's Hospital Augsburg Germany

Czech Paediatric Haematology Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Oncology Laboratory of Cancer Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

Department of Pediatric Hemato Oncology Ospedale Bambino Gesù Rome Italy

Department of Pediatric Hemato Oncology Regina Margherita Children's Hospital Turin Italy

Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Vienna Austria

Department of Pediatric Hematology and Oncology University Childrens' Hospital of Münster Münster Germany

Department of Pediatric Hematology Oncology IRCCS 1 G Gaslini Genova Italy

Department of Pediatric Hematology Oncology Ospedale Pausillipon Naples Italy

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Department of Pediatrics University Medical Center Schleswig Holstein Campus Kiel Kiel Germany

Institute of Biostatistics and Clinical Research University of Münster Münster Germany

Medical Statistics Unit Department of Clinical Medicine and Prevention University of Milano Bicocca Milan Italy

Pediatric Hematology and Oncology Charité Berlin Germany

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Pediatric Hematology Oncology Unit Department of Pediatrics University of Milano Bicocca MBBM Foundation Monza Italy

Pediatrics 5 ; Stuttgart Cancer Center; Klinikum Stuttgart Olgahospital Stuttgart Germany

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