Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia H OWARD L. MC L EOD, 1 S ALLY C OULTHARD, 2 A NGELA E. T HOMAS , 3 S TUART C. P RITCHARD, 1 D EREK J. K ING , 4 S USAN M. R ICHARDS , 5 O. B. E DEN, 6 A NDREW G. H ALL 2 AND B RENDA E. S. G IBSON 7 1 Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, 2 Leukaemia Research Fund Laboratory, University of Newcastle-upon-Tyne, 3 Royal Hospital for Sick Children, Edinburgh, 4 Department of Haematology, Aberdeen Royal Infirmary, 5 Clinical Trials Service Unit, University of Oxford, 6 Manchester Children’s Hospital, Manchester, and 7 Royal Hospital for Sick Children, Glasgow Received 11 November 1998; accepted for publication 24 February 1999 Summary. The role of 6-mercaptopurine (6MP) in the treatment of childhood acute lymphoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP is significantly influenced by inactivation by the polymorphic enzyme thiopurine methyltransferase (TPMT). In the general population 89–94% have high TPMT activity, 6–11% have intermediate activity, and approximately 0·3% have low activity. Individuals with low-activity experience severe or fatal toxicity with standard 6MP doses. Prospective identi- fication of this group of patients might prevent this problem. Recent identification of the molecular basis for low TPMT activity enabled rapid assessment of altered 6MP metabolism by PCR methods. This study evaluated the frequency of mutant TPMT alleles in 147 children with ALL. One patient was homozygous mutant (0·7%), and 16 patients were heterozygous for variant TPMT alleles (10·9%). The majority of mutant alleles were TPMT*3A. Both the allele frequency and the pattern of TPMT mutations were similar to that observed in an adult British population. The number of weeks when 6MP therapy was adminis- tered at full dose was determined in patients on MRC UKALL X and XI. The 94 patients spent a median 11% of the maintenance period receiving no therapy as a result of haematological toxicity. There was no significant difference in the number of weeks when no therapy could be administered among patients with a wild-type or hetero- zygous genotype. However, the one patient with a homo- zygous mutant genotype had severe haematological toxicity and no therapy could be administered for 53% of the maintenance period. This study demonstrates that 11·6% of the children had variant TPMT alleles. Prospective identification of TPMT genotype may be a promising tool for decreasing excessive haematological toxicity in individuals with low activity. Keywords: thiopurine methyltransferase, acute lympho- blastic leukaemia, pharmacogenetics, 6-mercaptopurine. The thiopurines, 6-mercaptopurine (6MP) and thioguanine (TG), are the backbone of current therapy for childhood acute lymphoblastic leukaemia (ALL). In standard protocols, 6MP or TG is administered as a daily oral dose during maintenance therapy (Chessells et al, 1997; Evans et al, 1998; Lancaster et al, 1998). The efficacy of 6MP is significantly influenced by activation to cytotoxic thio- guanine nucleotides (TGN) (McLeod, 1997). Alternatively, 6MP is inactivated by the polymorphic enzyme thiopurine methyltransferase (TPMT), whereby 89–94% of the population has high activity, 6–11% have intermediate activity, and rare individuals (0·3%) have very low activity (Lennard et al, 1990; McLeod et al, 1994, 1995b). Patients with low TPMT activity experience severe or fatal haematological toxicity when administered standard 6MP doses (McLeod et al, 1993; Schutz et al, 1993). TPMT activity also influences clinical outcome, in that ALL patients with high TPMT activity have a poor long-term survival compared with those with lower TPMT activity (Lilleyman & Lennard, 1994). This relationship has led to a call for prospective assessment of TPMT activity prior to initiation of therapy (Jackson et al, 1997). However, many children with ALL require red cell transfusion at presentation, often prior to referral to the treatment centre (McLeod et al, 1995b). The British Journal of Haematology , 1999, 105, 696–700 696  1999 Blackwell Science Ltd Correspondence: Dr Howard L. McLeod, Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD. e-mail: h.l.mcleod@abdn.ac.uk.