Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia

The role of 6-mercaptopurine (6MP) in the treatment of childhood acute lymp hoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP is significantly influenced by inactivation by the polymorphic enzyme thio purine methyltransferase (TPMT). In the general population 89-94% have high TPMT activity, 6-11% have intermediate activity, and approximately 0.3% ha ve low activity, Individuals with low-activity experience severe or fatal t oxicity with standard 6MP doses. Prospective identification of this group o f 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 evalu ated the frequency of mutant TPMT alleles in 147 children with ALL. One pat ient was homozygous mutant (0.7%), and 16 patients were heterozygous for va riant TPMT alleles (10.9%). The majority of mutant alleles were TPMT*3A. Bo th the allele frequency and the pattern of TPMT mutations were similar to t hat observed in an adult British population. The number of weeks when GMP therapy was administered at full dose was dete rmined 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 haematologi cal toxicity. There was no significant difference in the number of weeks wh en no therapy could be administered among patients with a wild-type or hete rozygous genotype. However, the one patient with a homozygous mutant genoty pe 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 d ecreasing excessive haematological toxicity in individuals with low activit y.