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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1812-1821
Acute Lymphoblastic Leukemia
Asparagine levels in the cerebrospinal fluid
of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study
Carmelo Rizzari,1^ Claudia Lanvers-Kaminsky,2^ Maria Grazia Valsecchi,3
Andrea Ballerini,4 Cristina Matteo,4 Joachim Gerss,5 Gudrun Wuerthwein,2
Daniela Silvestri,3 Antonella Colombini,1 Valentino Conter,1 Andrea Biondi,1
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Martin Schrappe, Anja Moericke, Martin Zimmermann, Arend von
Stackelberg,8 Christin Linderkamp,9 Michael C. Frühwald,10 Sabine Legien,11 Andishe Attarbaschi,12 Bettina Reismüller,12 David Kasper,13 Petr Smisek,14 Jan Stary,14 Luciana Vinti,15 Elena Barisone,16 Rosanna Parasole,17 Concetta Micalizzi,18 Massimo Zucchetti4* and Joachim Boos2*
1Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano- Bicocca, MBBM Foundation, Monza, Italy; 2Department of Pediatric Hematology and Oncology, University Childrens’ Hospital of Münster, Münster, Germany; 3Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy; 4Department of Oncology, Laboratory of Cancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; 5Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany; 6Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; 7Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 8Pediatric Hematology and Oncology, Charité, Berlin, Germany; 9Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 10Children’s Hospital, Augsburg, Germany; 11Pediatrics 5 (Oncology, Hematology, Immunology); Stuttgart Cancer Center; Klinikum Stuttgart – Olgahospital, Stuttgart, Germany; 12Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria; 13Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; 14Czech Paediatric Haematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic; 15Department of Pediatric Hemato-Oncology, Ospedale Bambino Gesù, Rome, Italy; 16Department of Pediatric Hemato-Oncology, Regina Margherita Children’s Hospital, Turin, Italy; 17Department of Pediatric Hematology-Oncology, Ospedale Pausillipon, Naples, Italy and 18Department of Pediatric Hematology-Oncology, IRCCS I.G. Gaslini, Genova, Italy.
^CR and CL-K share first authorship. *MZ and JB share last authorship.
ABSTRACT
Asparagine levels in cerebrospinal fluid and serum asparaginase activ- ity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intra- venously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cere- brospinal 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 cere- brospinal 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,
Correspondence:
CARMELO RIZZARI
c.rizzari@asst-monza.it
Received: September 14, 2018. Accepted: January 31, 2019. Pre-published: January 31, 2019.
doi:10.3324/haematol.2018.206433
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1812
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