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Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

Ebbesen, Maria S. MD; Nygaard, Ulrikka MD, PhD; Rosthøj, Susanne MSc, PhD; Sørensen, Ditte MSc; Nersting, Jacob MSc, PhD; Vettenranta, Kim MD, PhD; Wesenberg, Finn MD, DMSc; Kristinsson, Jon MD; Harila-Saari, Arja MD, PhD; Schmiegelow, Kjeld MD, DMSc

Journal of Pediatric Hematology/Oncology: April 2017 - Volume 39 - Issue 3 - p 161–166
doi: 10.1097/MPH.0000000000000733
Original Articles

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 (r s=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 WT) 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 WT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.

*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

On behalf of the Nordic Society of Pediatric Hematology and Oncology (NOPHO).

Supported by the Danish Cancer Society (grant no. 9710030), The Danish Childhood Cancer Foundation, The Children’s Cancer Foundation, Sweden (grant no. 1999/080), The National Medical Research Council (grant no. 22-2-0305), The Nordic Cancer Union, The Lundbeck Foundation (grant nos.: 30/98 and 38/99), The Otto Christensen Foundation, The Gangsted Foundation, and The Gunnar Jørgensen Foundation.

The authors declare no conflict of interest.

Reprints: Kjeld Schmiegelow, MD, DMSc, Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Copenhagen, Denmark (e-mail:

Received April 4, 2016

Accepted November 30, 2016

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