{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:12:18Z","timestamp":1789017138642,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T00:00:00Z","timestamp":1492560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010733","name":"B\u00f8rnecancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010733","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6\u2010thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG\u2010asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG\u2010asparaginase, combined with other drugs, may trigger SOS during 6\u2010thioguanine\u2010free maintenance therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)\/6\u2010mercaptopurine (6MP) maintenance therapy that included PEG\u2010asparaginase until week 33 (randomized to two\u2010 vs. six\u2010week intervals), as well as alternating high\u2010dose MTX or vincristine\/dexamethasone pulses every four weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 130 children receiving PEG\u2010asparaginase biweekly, 29 developed SOS (\u22652 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain \u22652.5%, unexplained thrombocytopenia &lt;75 \u00d7 10<jats:sup>9<\/jats:sup> l<jats:sup>\u20131<\/jats:sup>) at a median of 30 days (interquartile range [IQR]: 17\u201366) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty\u2010six cases (90%) occurred during PEG\u2010asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (<jats:italic>P<\/jats:italic> = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG\u2010asparaginase compared to after its discontinuation. Time\u2010dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol\/mmol hemoglobin increase, 95% confidence interval: 1.05\u20131.14). Six\u2010week PEG\u2010asparaginase intervals significantly reduced SOS\u2010specific hazards (<jats:italic>P<\/jats:italic> &lt; 0.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>PEG\u2010asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.26519","type":"journal-article","created":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T17:10:06Z","timestamp":1492621806000},"source":"Crossref","is-referenced-by-count":33,"title":["Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites"],"prefix":"10.1002","volume":"64","author":[{"given":"Linea Natalie","family":"Toksvang","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"De Pietri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stine N.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Nersting","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitte K.","family":"Albertsen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peder S.","family":"Wehner","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology H. C. Andersen Children's Hospital Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steen","family":"Rosth\u00f8j","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Aalborg University Hospital  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi M.","family":"L\u00e4hteenm\u00e4ki","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine Turku University Hospital  Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Astrid Lindgrens Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tove A.","family":"Nystad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Hospital North Norway  Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrine","family":"Grell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"},{"name":"Section of Biostatistics Department of Public Health University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Frandsen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjeld","family":"Schmiegelow","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet  Copenhagen Denmark"},{"name":"Institute of Clinical Medicine, The Faculty of Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.1636"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22719"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2002-23204"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2006.02742.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-8327-5_2"},{"issue":"10","key":"e_1_2_8_7_1","first-page":"1396","article-title":"A prospective survey on incidence, risk factors and therapy of hepatic veno\u2010occlusive disease in children after hematopoietic stem cell transplantation","volume":"90","author":"Cesaro S","year":"2005","journal-title":"Haematologica"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69558-5"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-230656"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.37"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPH.0000000000000206"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2013.07.010"},{"issue":"2","key":"e_1_2_8_13_1","first-page":"351","article-title":"Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture","volume":"48","author":"Kano Y","year":"1988","journal-title":"Cancer Res"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.13.8404"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.12097"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12733"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2013.09.027"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25319"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.12562"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30035-3"},{"issue":"3","key":"e_1_2_8_21_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1093\/clinchem\/44.3.551","article-title":"Simultaneous determination of 6\u2010thioguanine and methyl 6\u2010mercaptopurine nucleotides of azathioprine in red blood cells by HPLC","volume":"44","author":"Dervieux T","year":"1998","journal-title":"Clin Chem"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2011.11.032"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1373\/49.2.260"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-012-6581-7"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(97)90152-1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800100286"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-4811-9_69"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26139"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403783"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840040121"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198712000-00011"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2009.08.024"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-08-2372"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(93)90534-4"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-009-1184-5"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.81"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2003.12.001"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07765.x"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402990"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-015-2717-8"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpbc.26519","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.26519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T23:35:01Z","timestamp":1696376101000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.26519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,19]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1002\/pbc.26519"],"URL":"https:\/\/doi.org\/10.1002\/pbc.26519","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,19]]},"article-number":"e26519"}}