title: Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia.
abstract: Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.
authors.affiliation: *Department of Pediatrics and Adolescent Medicine, Rigshospitalet †Section of Biostatistics, Department of Public Health #The Institute Clinical Medicine, University of Copenhagen, Copenhagen Denmark ‡Department of Pediatrics, University Hospital, Tampere, Finland §Department of Pediatrics, The University Hospital, Oslo, Norway ∥Department of Pediatrics, University Hospital, Reykjavik, Iceland ¶Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institutet, Solna, Stockholm, Sweden.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Ebbesen
authors.forename: Ulrikka
authors.initials: U
authors.lastname: Nygaard
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosthøj
authors.forename: Ditte
authors.initials: D
authors.lastname: Sørensen
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.forename: Kim
authors.initials: K
authors.lastname: Vettenranta
authors.forename: Finn
authors.initials: F
authors.lastname: Wesenberg
authors.forename: Jon
authors.initials: J
authors.lastname: Kristinsson
authors.forename: Arja
authors.initials: A
authors.lastname: Harila-Saari
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D060046:Maintenance Chemotherapy / Q000009:adverse effects*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D008727:Methotrexate / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D008780:Methyltransferases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000188:drug therapy*; D011379:Prognosis
chemical_list: D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D000410:Alanine Transaminase; D008727:Methotrexate