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 (TPMTWT) 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 TPMTWT 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: firstname.lastname@example.org).
Received April 4, 2016
Accepted November 30, 2016