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Pharmacogenomics

Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

Abstract

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.

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Acknowledgements

This study has received financial support from The Childhood Cancer Foundation, Denmark; The University Hospital Rigshospitalet; The Children's Cancer Foundation of Sweden (Grant no.: 53/91, 62/94, 72/96, 98/59, 04/002), The Danish Cancer Society (Grant no.: 91-048, 92-017, 93-017, 95-100-28), The Lundbeck Foundation (Grant no.: 38/99), Novo Nordic Foundation, Home Secretary Research Grant for Individualized Therapy, Danish Research Council for Health and Disease, Michael Goldschmidt Holding A/S, The Nordic Cancer Union (Grant no.: 56-9257, 56-100-03-9102), and the United States National Institutes of Health (Grant No.: R01-GM28157, U01 GM61388). Kjeld Schmiegelow holds the Childhood Cancer Foundation Research Professorship in Pediatric Oncology. We thank all the Nordic pediatric oncology centers that have supported this study with blood sampling and detailed registration of the treatment data. Kjeld Schmiegelow designed the study and wrote the paper. Richard Weinshilboum performed most of the TPMT analyses, whereas Kjeld Schmiegelow performed the rest of the pharmacological analyses. Erik Forestier scrutinized the karyotypes of all patients. Jon Kristensen, Stefan Söderhäll, Kim Vettenranta, and Finn Wesenberg were responsible for providing the clinical data and follow-up data for patients from Iceland, Sweden, Finland, and Norway, respectively. All authors commented and approved the final paper.

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Schmiegelow, K., Forestier, E., Kristinsson, J. et al. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 23, 557–564 (2009). https://doi.org/10.1038/leu.2008.316

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