Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with PEG-Asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

Carmelo Rizzari, Claudia Lanvers-Kaminsky, Maria Grazia Valsecchi, Andrea Ballerini, Cristina Matteo, Joachim Gerss, Gudrun Wuerthwein, Daniela Silvestri, Antonella Colombini, Valentino Conter, Andrea Biondi, Martin Schrappe, Anja Moericke, Martin Zimmermann, Arend Von Stackelberg, Christin Linderkamp, Michael C Frühwald, Sabine Legien, Andishe Attarbaschi, Bettina ReismüllerDavid Kasper, Petr Smisek, Jan Stary, Luciana Vinti, Elena Barisone, Rosanna Parasole, Concetta Micalizzi, Massimo Zucchetti, Joachim Boos

Research output: Contribution to journalArticlepeer-review

Abstract

Asparagine levels in cerebrospinal fluid and serum asparaginase activities were monitored in children with acute lymphoblastic leukemia treated with PEG-asparaginase. The drug was given intravenously at 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were centrally analyzed. Since physiological levels of asparagine in cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when ≤0.2 μmol/L, i.e. below the lower limit of quantitation of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (686 day 33 and 217 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 a 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 PEG-Asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum PEG-Asparaginase activity levels resulting in a complete cerebrospinal fluid asparagine depletion was identified. The results consistently found in the two independent data sets strengthen the observations of this study.

Original languageEnglish
JournalHaematologica
DOIs
Publication statusE-pub ahead of print - Jan 31 2019

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