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Background: 6-mercaptopurine has been a standard component of long-term continuing treatment for childhood lymphoblastic leukaemia, whereas 6-thioguanine has been mainly used for intensification courses. Since preliminary data have shown that 6-thioguanine is more effective than 6-mercaptopurine, we compared the efficacy and toxicity of the two drugs for childhood lymphoblastic leukaemia., Methods: Consecutive children with lymphoblastic leukaemia diagnosed in the UK and Ireland between April, 1997, and June, 2002, were randomly assigned either 6-thioguanine (750 patients) or 6-mercaptopurine (748 patients) during interim maintenance and continuing therapy. All patients received 6-thioguanine during intensification courses. We analysed event-free and overall survival on an intention-to-treat basis. We obtained toxicity data using an adverse-event reporting system, with follow-up questionnaires to seek detailed information for specific toxicities. This trial is registered with the International Standard Randomised Controlled Number 26727615 with the name ALL97., Findings: After a median follow up of 6 years, there was no difference in event-free or overall survival between the two treatment groups. Although 6-thioguanine conferred a significantly lower risk of isolated CNS relapse than did 6-mercaptopurine (odds ratio [OR] 0.53, 95% CI 0.30-0.92, p=0.02), the benefit was offset by an increased risk of death in remission (2.22, 1.20-4.14, p=0.01), mainly due to infections during continuing therapy. Additionally, 95 patients developed veno-occlusive disease of the liver. Of these, 82 were randomly assigned 6-thioguanine, representing 11% of all 6-thioguanine recipients. On long-term follow-up, about 5% of 6-thioguanine recipients have evidence of non-cirrhotic portal hypertension due to periportal liver fibrosis or nodular regenerative hyperplasia., Interpretation: Compared with 6-mercaptopurine, 6-thioguanine causes excess toxicity without an overall benefit. 6-mercaptopurine should remain the thiopurine of choice for continuing therapy of childhood lymphoblastic leukaemia.

Many months' treatment with daily oral mercaptopurine is an important part of therapy for nearly all children with lymphoblastic leukaemia (ALL). Even when prescribed the same dose based on body surface area, patients have widely different intracellular concentrations of drug metabolites. Whether this variation matters in terms of disease control is not yet clear. To find out, we followed up a large group of children with ALL in whom mercaptopurine-derived thioguanine nucleotides in the red cells were measured during treatment with an identical dose of mercaptopurine early in first remission. 172 unselected children (100 boys, 72 girls) were recruited between 1980 and 1992. At median follow-up of 5 years from diagnosis 42 (24%) had relapsed; 30 had erythrocyte thioguanine nucleotide concentrations below the group median (284 pmol per 8 x 10(8) erythrocytes) and 12 had values above the median. The actuarial relapse-free survival at 5 years was 63% in the below-median group and 84% in the above-median group (difference 21% [95% CI 3-39%], p = 0.0018). Multivariate analysis showed that erythrocyte thioguanine nucleotide concentration was independent of other prognostic variables including age, leukaemia immunophenotype, white-blood-cell count at diagnosis, trial protocol, and sex. Whatever the cause, in childhood ALL variable formation of intracellular mercaptopurine metabolites seems to be clinically important. Therapeutic schedules that include long-term daily oral mercaptopurine might be more effective if such metabolites are monitored.

6-mercaptopurine (6-MP) can be inactivated by S-methylation, which is catalysed by thiopurine methyltransferase (TPMT). An alternative metabolic route leads to the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). To investigate whether these two pathways compete with each other to affect the therapeutic response to 6-MP, 6-TGN concentrations and TPMT enzymatic activity were measured in erythrocytes (RBC) from 95 children on long-term 6-MP therapy for lymphoblastic leukaemia (ALL). RBC TPMT activities were also measured in 130 control children and 104 long-term survivors of ALL no longer on treatment. The 95 children on 6-MP showed wide interindividual differences in RBC 6-TGN concentrations at the full protocol dose of 75 mg/m2, and RBC 6-TGN concentrations correlated negatively with RBC TPMT activity. Children with 6-TGN concentrations below the group median had higher TPMT activities and a higher subsequent relapse rate. 50 of the 104 long-term survivors had been treated with "gentle" low-dose protocols, and this subgroup contained an excess of children with lower TPMT activities compared with normal controls. These results indicate that genetically determined TPMT activity may be a substantial regulator of the cytotoxic effect of 6-MP, an effect which in turn could be important in influencing the outcome of therapy for childhood ALL.