1. ¹The Institute of Gynecology, Obstetrics, and Pediatrics, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
2. ²Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark
3. ³Department of Pediatrics, University Hospitals, Umeå, Sweden
4. ⁴Department of Pediatrics, University Hospitals, Landspitalin Reykjavik, Iceland
5. ⁵Department of Pediatrics, University Hospitals, Astrid Lindgrens Barnsjukhus, Stockholm, Sweden
6. ⁶Department of Pediatrics, University Hospitals, Helsinki, Finland
7. ⁷Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA
8. ⁸Department of Pediatrics, University Hospitals, National Hospital, Oslo, Norway

Correspondence: Professor K Schmiegelow, The Pediatric Clinic, Juliane Marie Center, University Hospital Rigshospitalet, Blegdamsvej 9, Section 5704, 2100 Copenhagen, Denmark. E-mail: kschmiegelow@rh.dk

Received 30 July 2008; Revised 11 September 2008; Accepted 19 September 2008; Published online 6 November 2008.

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.